Methods for treating skin

ABSTRACT

Provided are methods of treating skin with at least two alternating treatment modalities to improve the health and/or diminish signs of aging. Some methods according to the present invention may comprise topically applying at least two separate compositions, in a sequential, rotating, or alternating fashion to overcome adaptation, tolerance, or sensitization phenomena.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) to U.S.Provisional patent application Ser. No. 62/128,647, filed Mar. 5, 2015,the entire contents of which are hereby incorporated by referenceherein.

FIELD OF INVENTION

The invention relates generally to methods for reducing signs of agingand/or improving the health of human skin. More particularly, theinvention relates to rotational, serial or alternating use of two ormore different treatments to improve the appearance of skin, includingremediating the signs of aging. The two or more two different treatmentmodalities may comprise, without limitation, topical application ofcompositions containing skincare actives, use of devices, for example,to impart mechanical or electromagnetic energy to the skin, applicationof masks (which may be active-eluting), subcutaneous injection, oraladministration of actives, and chemical peels. The treatment modalitiesmay be carried out at least once a day for a treatment period that mayrange from 1-31 days, and then the treatment modalities are alternatedor rotated serially.

BACKGROUND

Numerous skincare products have been developed for improving theappearance of human skin. Many of the more effective methods employtopically applied compositions containing one or more active ingredientsknown to beneficially affect the skin. For example, compositionscontaining retinoids, particularly retinol, have proven to be effectivein combatting fine lines, wrinkles and other indications of skin agingsuch as sagging. Topically applied retinoids promote the formation ofcollagen and elastin in the skin. Compositions having retinoids may beused to treat a myriad of unwanted skin conditions, such as acne andwrinkles. However, the benefits of retinol therapy are known to plateauwith prolonged use in some individuals.

Phytol is another active agent that is known to promote skin health andremediate or diminish signs of skin aging. A composition for enhancingthe appearance of skin comprising both phytol and retinol is describedin U.S. Pub. 2003/0198657 to Menon, the disclosure of which is herebyincorporated by reference herein.

It has been recognized that skin may become accustomed to cosmeticproducts, and the observable benefits to skin may begin to decline afteran initial period of treatment. It has also been observed bydermatologists in clinical trials that skin can build up a tolerance toretinoids, and using higher concentrations of retinoid-containingcompositions over time might be needed to maintain the desiredeffectiveness in some individuals. This phenomenon is analogous toadaptation, which is well-described in biological systems. For example,on a cellular level, stimulation of receptors leads to desensitizationand a decreased response. A period of resensitization or “rest” isneeded before the same level of response can be seen again.

It is therefore an object of the present invention to provide methods oftreating skin that overcome the tolerance problem and/or provideenhanced efficacy and/or improve the health and/or appearance of humanskin. It is a further object of the present invention to providetreatments for human skin involving the rotational, serial and/oralternating use of at least two distinct treatment modalities. It is afurther object of the present invention to provide methods for improvingthe health and/or appearance of human skin involving the rotational,serial and/or alternating topical application of at least two skincarecompositions.

The foregoing discussion is presented solely to provide a betterunderstanding of nature of the problems confronting the art and shouldnot be construed in any way as an admission as to prior art nor shouldthe citation of any reference herein be construed as an admission thatsuch reference constitutes “prior art” to the instant application.

SUMMARY OF INVENTION

In accordance with the foregoing objectives and others, the presentinvention provides methods for improving one or more signs ofdermatological aging of human skin and/or improving the health of humanskin, the methods comprising alternating/rotating between a plurality(e.g., two, three, four, five, six, seven, or more) different treatmentmodalities. Each treatment modality is administered for a period of time(e.g., at least once daily for 1-31 days), which may be the same ordifferent from the period of time of treatment for each of the othertreatment modalities. The treatment modalities may include applicationof topical compositions to the skin, application of mechanical orelectromagnetic energy (e.g., ultrasound, vibration, light (visible,infrared, etc.)) to the skin, mechanical or chemical desquamation (e.g.,microdermabrasion, chemical peel, etc.), application of masks to theskin (which may optionally elute skincare actives to the skin), oraladministration of actives, etc. The treatment modality may includeallowing the skin to “rest,” by not treating it in any particularmanner, other than customary routine washing and/or moisturizing. Insome implementations, at least one of the plurality of treatmentmodalities entails topical application of a skincare active ingredientto an area of skin (e.g., the face) at least once daily for a period of1-31 days. In some implementations, at least two of the pluralitytreatment modalities entail topical application of a skincare activeingredient to an area of skin (e.g., the face) at least once daily for aperiod of 1-31 days, wherein the skincare actives and treatment periodsmay be different from one another. In some implementations, at least oneof the plurality of treatment modalities entails application ofmechanical or electromagnetic energy to an area of skin (e.g., the face)at least once daily for a period of 1-31 days. In some implementations,at least one of the plurality treatment modalities entails exfoliation(e.g., chemical or mechanical) of an area of skin (e.g., the face) atleast once daily for a period of 1-31 days, for example, using achemical peel (e.g., phenol), microdermabrasion, or with a topicalcomposition comprising an effective amount of a desquamating agent. Insome implementations, the method comprises the use of at least twotreatment modalities, wherein a first composition is applied topicallyto an area of skin (e.g., the face) one or more times daily for a firstperiod of time (e.g., 1-31 days), followed by topical application to thesame area of skin of a second composition one or more times daily for asecond period of time (e.g., 1-31 days).

Without wishing to be bound by any particular theory, it is believedthat the rotational treatment regimen overcomes, at least in part,adaptation and/or toleration phenomena whereby the effect of certainactives or treatments diminishes or plateaus over time. It is alsotheorized that the rotational treatments may act cooperatively and/orsynergistically whereby one treatment modality enhances the efficacy ofthe other. For example, a desquamation treatment is contemplated toimprove penetration of a subsequently applied active, or ananti-inflammatory treatment is contemplated to reduce erythemaassociated with retinol use and consequently permit higher levels ormore frequent application of retinoids.

In one aspect of the invention, methods of treating skin to improve thehealth and/or appearance thereof are provided comprising administering afirst treatment modality (e.g., topically applying a first compositioncomprising an active agent) to an area of skin in need thereof at leastonce daily for a first period of time (e.g., a predetermined period oftime), typically from 1-31 days, or from 2-31 days, or from 3-31 days,or from 4-31 days, or from 5-31 days, or from 6-31 days, or from 7-31days, or from 1-7 days, or from 2-7 days, or from 3-7 days, or from 4-7days, or from 5-7 days, or 7 days, etc. The period of time may be“predetermined,” by which is meant that prior to beginning the regimenthe user determines or is instructed (e.g., by written instructionaccompanying the product or obtained electronically on a computer) touse the treatment modality (e.g., topically apply a skincarecomposition) daily for a fixed number of consecutive days.Alternatively, the period of time may be determined by the user'sresponse and/or reaction to daily use of the first treatment modality(e.g., topical application of the first composition). For example, thefirst period of time may begin on the first day ofadministration/application and end on the appearance of irritationand/or redness, or may end on when there are observable improvementsand/or reductions in a sign of skin aging, or may end on the onset of anefficacy plateau, etc. In some implementations, the first treatmentmodality (e.g., topical application of a skincare composition) is usedon the same area of skin for at least two, three, four, five, six, sevenor more consecutive days. In other implementations, the first treatmentmodality (e.g., topical application of a skincare composition) is usedfor only one day. In other implementations, the first treatment modality(e.g., topical application of a skincare composition) is used daily forseven days.

The first period of time may be followed by a second period of time inwhich the first treatment modality is discontinued and/or use of asecond treatment modality is initiated. For example the first treatmentmodality may comprise topical application of a first composition(comprising a first active agent) for a first period of time, andthereafter: (i) the first composition is not topically applied to thesame area of skin daily for a second period of time, (ii) the firstcomposition continues to be applied to the same area of skin daily butin altered amounts (e.g., the dose (mg/cm²) is increased or decreasedrelative to the first period of time) or altered frequency (e.g.,applied more times or less times per day relative to the first period oftime) for a second period of time, and/or (iii) a second composition istopically applied (e.g., at least once daily) to the same area of skinfor a second period of time. In one embodiment, the first treatmentmodality is discontinued during the second period of time.

The second period of time is typically from 1-31 days, or from 2-31days, or from 3-31 days, or from 4-31 days, or from 5-31 days, or from6-31 days, or from 7-31 days, or from 10-31 days, or from 14-31 days, orfrom 5-31 days, or from 6-31 days, or from 7-31 days, or from 1-7 days,or from 2-7 days, or from 3-7 days, or from 4-7 days, or from 5-7 days,or from 7 days, etc. In some implementations, a second treatmentmodality (e.g., topical application of a skincare composition) isadministered to the same area of skin for at least one, two, three,four, five, six, seven or more consecutive days. In some embodiments thesecond period of time is shorter than, equal to, or longer than thefirst period of time. In some embodiments, the second period of time isone day. In some embodiments the second period of time is seven days.The second period of time may be predetermined (e.g., according towritten instructions) or may be determined by the user's response and/orreaction to daily use/application of the second treatment modality. Thesecond period of time typically begins on the day following the last dayof the first period of time, although it is contemplated that the end ofthe first period of time and the beginning of the second period of timemay be separated by one, two, three, four, five, six, or seven days ormore, which may be a predetermined period of time, for the skin to“rest” without treatment with the first or second treatment modalities.This could entail treating the skin only with a composition having noskin actives (e.g., with only moisturizer treatment) or applying nothingat all during that time. It is also contemplated that the second periodof time may partially (but not completely) overlap with the first periodof time such that the first and second modalities are administered tothe same area of skin daily for a number of days (e.g., one day, twodays, three, days, etc.). The second period of time may thereforeoverlap with, be subsumed by, or be consecutive with the first period oftime, or may follow the first period of time after an interval of a dayor more. The second treatment modality may comprise topical applicationof a second skincare composition that is different from the firstskincare composition. For example, if the first skincare compositioncomprises an effective amount of a retinoid (e.g., retinol), then thesecond skincare composition may, in some embodiments, comprise adifferent retinoid, a different amount of the same retinoid, or may befree of retinoids (e.g., retinol). In some implementations, the secondtreatment regimen may entail the absence of treatment, by which is meantthat no composition is topically applied to the skin. To illustrate, onetreatment regimen according to the invention may comprise alternatingbetween a first modality comprising topical application of a retinolformulation, followed by a second modality comprising topicalapplication of a second formulation that does not comprise retinol (orany retinoid), and thereafter repeating those steps one or moreadditional times.

After completion of the second treatment modality, the regimen maycontinue with re-administration of the first treatment modality to thesame area of skin for said first period of time. The first period oftime may commence on the day following the last day of the second periodof time. Alternatively, the second period of time may be followed by a“rest” period (as described above) prior to commencing the firsttreatment modality. In another embodiment, the second treatment modalitymay be followed (on the next day or after any period of “rest”) by athird treatment modality for a third period of time.

The regimen may continue in this fashion using any number of treatmentmodalities. For example, in one embodiment of the invention, sevendifferent treatment modalities are administered to the individual forseven periods of time in sequence. The periods of time according to thisembodiment may range from 1-31 days, more typically, from 1-7 days, orfrom 1-3 days, or 1 day. In one embodiment, the treatment regimencomprises seven different treatment modalities, each of which areadministered for at least one day (or for only one day) during a periodof seven consecutive days, with the proviso that no two days have theidentical treatment regimen.

In various embodiments in which two treatment modalities are employed,the modalities may be indicated as “A” and “B,” respectively, where “A”,“B” may each represent a topical composition, identify a treatmentmaterial or materials and/or modality of treatment administration,duration, intensity, etc., repeated at different intervals (perapplication; per day; per week; etc.). In some embodiments, thetreatment regimen may be represented as (AB)_(n), where modalities A andB are employed sequentially, and then the process is repeated n−1 times(where n is typically greater than 2, or greater than 3, or greater than4, or greater than 8, or greater than 12, etc.). For example, in thecase where n=4, this may be represented as ABABABAB. Additionaltreatment modalities may also be included. For example, in the casewhere a third treatment modality “C” is included, the regimen mayrepresented as (ABC)_(n), where modalities A, B, and C are employedsequentially, and then the process is repeated n−1 times. For example,in the case where n=4, this may be represented as ABCABCABCABC.Additional treatment modalities may also be included. In anotherembodiment, the treatment modalities may be interspersed with restperiods in which no actives or non-active skin care formulations areutilized.

In some embodiments, at least one of the pluralities of treatmentmodalities comprises topical application of a composition comprising aneffective amount of at least one skincare active. The active is usuallydissolved or dispersed in a physiologically compatible carrier (e.g., anemulsion, oil, gel, serum, etc.). The effective amount of the activemay, for example, comprise from about 0.0001% to about 25% (w/w) basedon the weight of the entire composition, more typically, from about0.001% to about 5% by weight (or from about 0.01-1% or 0.1-0.5% byweight). The composition may include additional adjuvants andexcipients, such as film formers, oils, resins, elastomers, waxes,thickeners and rheology modifiers, gellants, stabilizers, emollients,conditioning agents, humectants, chelating agents, pH adjusters,preservatives, fragrances, fillers and powders, colorants and opticalmodifiers, sunscreens, etc. The vehicle may comprise water or it may beanhydrous or substantially anhydrous. The vehicle may comprise one ormore oils, including ester oils, vegetable oils, fatty alcohols,hydrocarbon oils, mineral oils, polyolefin oils, silicone oils, and thelike.

In one embodiment, at least one of the plurality of treatment modalitiescomprises topical application of a composition comprising an effectiveamount (e.g., from about 0.05% to about 5% (w/w)) retinoid (e.g.,retinol, retinaldehyde, retinyl palmitate, etc.) at least once daily (oronce daily, etc.) for a first period of time from 1 day to 31 days, moretypically, from 2-31 days, or from 3-14 days, or from 5-10 days, or for7 days. In one implementation, the first composition comprises aneffective amount of a retinoid (e.g., retinol). In anotherimplementation, the second composition comprises an effective amount ofa retinoid (e.g., retinol). In one implementation, the first compositioncomprises an effective amount of a retinoid (e.g., retinol) and thesecond composition does not comprise an effective amount (e.g., fromabout 0.05% to about 5% (w/w)) of retinoid (e.g., retinol). In anotherimplementation, the second composition comprises an effective amount ofa retinoid (e.g., retinol) and the first composition does not comprisean effective amount (e.g., from about 0.05% to about 5% (w/w)) ofretinoid (e.g., retinol).

In some implementations, at least one of the plurality of treatmentmodalities entails topical application of an effective amount of aretinoid (e.g., retinol), at least once daily (or once daily) for afirst period of time from 1 day to 31 days, or from 2-31 days, or from3-14 days, or from 5-10 days, or from 1-7 days or from 1-5 days, or from1-3 days, or for one day. In one implementations, at least one of theplurality of treatment modalities entails topical application of aneffective amount of a retinoid (e.g., retinol), at least once daily (oronce daily, for example, at night) for seven consecutive days.

In one implementation, the first treatment modality (e.g., topicalapplication of a first composition comprising a skincare active) isadministered daily for five consecutive days (e.g., Monday-Friday) andthe second treatment modality (e.g., topical application of a secondcomposition comprising a different skincare active), which is differentfrom the first treatment modality, is administered daily for thefollowing two days (e.g., Saturday-Sunday). In another implementation,the first treatment modality (e.g., topical application of a firstcomposition comprising a skincare active) is administered daily forseven consecutive days (e.g., Monday-Sunday) and the second treatmentmodality (e.g., topical application of a second composition comprising adifferent skincare active), which is different from the first treatmentmodality, is administered daily for the following seven consecutive days(e.g., Monday-Sunday). The regimen may be repeated a plurality of times,including at least one, two, three, four or more additional times, andtypically until an improvement in the health and/or appearance of skinis noted. The first treatment modality may involve topical applicationof a composition comprising an effective amount (e.g., 0.05% to 5% byweight) of a retinoid, such as retinol or retinyl palmitate. The secondtreatment modality may involve topical application of a secondcomposition comprising, for example, an effective amount of a skin careactive other than a retinoid. In one implementation, the secondcomposition comprises an effective amount of alpha hydroxy acid. In oneimplementation, the second composition comprises an effective amount ofan antioxidant. In one implementation, the second composition comprisesan effective amount of a botanical extract (e.g., Tiliacora triandraextract, including hydroponically grown variants). In anotherimplementation, the second composition comprises moisturizers,emollients, and/or humectants and may comprise additional actives or maybe free of additional actives (e.g., phytol, glycolic acid, and/orniacinamide). In another implementation, the second composition does notcomprise an effective amount of retinoids (e.g., retinol) or is free ofretinoids (e.g., retinol).

In some embodiments, the first topical cosmetic composition may compriseat least one skin active that has the effect of improving the appearanceand/or health of skin, including, without limitation, diminishing theappearance of signs of skin aging (e.g., chronological, hormonal,environmental, and/or photo-aging). In some embodiments, the firstactive agent may be a substance (e.g., small molecule, amino acid,protein, peptide, nucleic acid, extract, etc.) that increases collagen,pro-collagen, elastin, glucosaminoglycan (GAG) and/or hyaluronic acidproduction in the skin and/or reduces pigmentation in the skin and/ormodulates (increases or decreases) lipolysis or lipogenesis inadipocytes. The active agent may be, without limitation, an agent thatimproves tautness of skin (e.g., reduces sagging), diminishes theappearance of wrinkles and/or fine lines (e.g., crow's feet, feathering,etc.), thickens thinning skin, improves (e.g., evens out) skin tone,reduces the appearance of localized areas of pigmentation (e.g., sunspots, freckles, liver spots, age spots, etc.), reduces the appearanceof dark circles under the eyes, and/or reduces the appearance ofcellulite, etc. In some embodiments, the first composition may compriseone or more of the following: collagenase inhibitors, elastaseinhibitors, collagen upregulators/stimulators, pro-collagenupregulators/stimulators, elastase upregulators/stimulators, hyaluronicacid upregulators/stimulators, tyrosinase inhibitors, melanosometransferase inhibitors, melanogenesis inhibitors.

In some embodiments, the active agents may comprise one or more of thefollowing: retinoids (e.g., retinol and C₂₋₂₀ esters thereof, such asretinol palmitate, retinol acetate and retinol propionate,retinaldehyde, 9-cis retinoic acid, 13-cis retinoic acid, all-transretinoic acid, phytanic acid, Vitamin A, and esters and salts of any ofthese, etc.), α-hydroxy acids (e.g., glycolic acid, lactic acid, citricacid, etc.), β-hydroxy acids (e.g., salicylic acid), salicylates,5-α-reductase inhibitors (linolenic acid, linoleic acid, finasteride,etc.), vitamins (e.g., vitamins A, B, C, E, etc., and C₂₋₂₀ estersthereof), PPAR-γ inhibitors, anti-inflammatories (e.g., TNF-αinhibitors), antioxidants (e.g., ascorbic acid, astaxanthin,beta-carotene, catechins, curcumin, ellagic acid and gallic acidderivatives (e.g., propyl gallate), ferulic acid derivatives (e.g. ethylferulate, sodium ferulate), glutathione (GSH), green tea extract,hexylresorcinol, idebenone, α-lipoic acid, lycopene, phytol, phytanicacid, TDPA and esters (e.g., dilauryl) thereof, thioglycolic acid,reductic acid; rosmarinic acid; tannic acid; tetrahydrocurcumin;tocopherol and its derivatives, ubiquinone, uric acidand C₂₋₂₀ esters ofany of the thereof), phytochemicals (e.g., flavonoids and carotenoids),phytoalexins, stilbenoids (e.g., resveratrol), botanicals, AdvancedGlycation End Product (AGE) inhibitors/reversers (e.g., TDPA), purines;estrogen synthetase stimulating compounds (e.g., xanthine and caffeineand derivatives), aminoacids (e.g., L-arginine, L-aspartic acid,L-glutamine, L-glycine, L-lysine, L-histidine, L-alanine, L-threonine,L-glutamic acid, L-taurine, L-proline, L-serine, etc., or C₂₋₂₀ estersor amides and derivatives thereof, including enantiomers) andderivatives thereof (e.g., carnitine, N-acetyl Tyrosinamide, etc.),di-peptides (e.g., carnosine), and oligopeptides and C₂₋₂₀ (e.g.,palmitoyl) esters or amides thereof (e.g., palmitoyl oligopeptides),desquamating agents (e.g., glycolic acid, salicylic acid,imidopercarboxylic acids, jasmonic acid, gentisic acid,3,6,9-trioxaundecanedioic acid, etc., and derivatives of any of these),keratolytics (e.g., allantoin, lactic acid, urea, etc.), astringents(e.g., Witch hazel), antipruritic agents (e.g., camphor, menthol, etc.),anti-acne agents (e.g., salicylic acid, sulfur, benzoyl peroxide,triclosan, etc.), steroids, including corticosteroids (e.g.,hydrocortisone) and sterols (e.g., β-sitosterols, phytosterols, such asGlycine soja sterols, pomegranate sterols, Brassica campestris sterols,canola sterols, etc.), soy isoflavone glycosides (e.g., genistin,daidzin, and glycitin) and aglycones (e.g., genistein, daidzein, andglycitein), depigmenting agents (e.g., hydroquinone, licorice extract,kojic acid, niacinamide, etc.), pigmenting agents (e.g.,dihydroxyacetone), barrier function enhancing agents (e.g., ceramides,such as ceramide-2, glycerides, cholesterol and its esters, alpha- andomega-hydroxy fatty acids and esters thereof, etc.), serine proteaseinhibitors (e.g., soy proteins), and combinations thereof.

In various, non-limiting embodiments, the active agent may be asubstance that modulates (e.g., upregulates, down regulates, stimulates,inhibits, etc.) expression or activity of one or more of the following:retinoic acid receptor (RAR), retinoid X receptor (RXR), Carnitinepalmitoyltransferase I (CPT-1), PLOD-2, Thymosin-β4, tenascin-X, WIPI-1,Nesprin-2, MAGP-1, tyrosinase, desmogleins 1 and 3, fibroblast growthfactors (FGFs), paxillin, collagen 1, C-Reactive Protein (CRP),Calcitonin gene related peptide (CGRP), sirtuins (SIRT1 protein),filbrillin-1, PPAR (e.g., α, γ, etc.) receptors, stearoyl CoA desaturase(SCD1), adiponectin, cyclooxygenase-2 (COX-2) enzyme, metallothioneins,Lysyl oxidase like-1 (LOXL1), β-1-integrin, cytokines (e.g., I-CAM,IFN-γ, IL1-β, IL12, IL6, IL8, IL2, IP10, TNF-α, TNFr2, etc.) histamine(e.g., H₁, H₂, etc.), adipose septa (e.g., receptorasporin, biglycan,decorin, dermatopontin, fibromodulin, fibronectin, galectin-1, lamininbeta 2, lumican, MAGP-4, mimecan (osteoglycin), nidogen-1, nidogen-2, orprolargin), DICKKOPF-1, paxillin, fibroblast growth factor receptor 1(FGFR1), alpha-2-adrenergic receptor, beta-adrenergic receptor,phosphodiesterase, adenylate cyclase activator, serine proteinase (e.g.,trypsin inhibitor, neutrophil elastase, etc.), matrix metalloproteinase(e.g., gelatinase B), fructosamine-3-kinase (FN3K or FN3K RP),matriptase MT/SP1, Monoamine Oxidase B (MAOB), growth factors (e.g.,bFGF, PDGF, VEGF, etc.), Human tissue Kallikreins (KLKs, e.g., KLK-5),Calcineurin, etc.

In some embodiments, either the first or second composition comprises aC₂₀-C₂₅ terpene alcohol (e.g., phytol) or a metabolite therefore (e.g.,phytanic acid). In some embodiments, either the first or secondcomposition comprises a retinoid (e.g., retinol or retinol palmitate).In some embodiments, either the first or second composition comprises aC₂₀-C₂₅ terpene alcohol (e.g., phytol) or a metabolite therefore (e.g.,phytanic acid) and the other composition comprises a retinoid (e.g.,retinol).

In some implementations, either the first or second compositioncomprises a C₂₀-C₂₅ terpene alcohol (e.g., phytol) or a metabolitetherefore (e.g., phytanic acid), and the other composition comprises aretinoid (e.g., retinol). The first and second compositions are appliedin a serial, sequential, rotating, and/or alternating fashion.Typically, the alternating treatments are carried out without a gap inbetween them, such that one begins on the day following the end of theother. Typically, the first period of time will be from about one day toabout one month (or from 3-20 days or from 5-10 days) and the secondperiod of time will be from about one day to about one month (or from3-20 days or from 5-10 days). The compositions may be applied in eitherorder (e.g., phytol treatment period followed by retinol treatmentperiod, or retinol treatment period followed by phytol treatmentperiod), and the method may be repeated any additional number of times(e.g., once, twice, thrice, etc.), to achieve any number of alternatingtreatments with said first and second compositions, and ideally for longenough to achieve a visible improvement in the health and/or appearanceof skin (e.g., a reduction in the number and/or depth of wrinkle or finelines). In some implementations, the treatment is continued for at least4 weeks, at least 8 weeks, at least 12 weeks, or more.

In one aspect, a method for diminishing the appearance of dermatologicalsigns of aging (e.g., fine lines and/or wrinkles and/or thinning skinand/or reducing unwanted pigmentation and hyperipgmentation and/orsagging skin, etc.) and/or improving the health of human skin (e.g.,improving barrier function, etc.) is provided, the method comprising thesteps of: (1) topically applying to an area of skin in need of suchtreatment an effective amount (e.g., from about 0.001-5% by weight) of aC₂₀-C₂₅ terpene alcohol (e.g., phytol) or metabolite therefore (e.g.,phytanic acid) containing composition for a first period of time (e.g.,1-31 days, or 3-20 days, or 5-10 days, or 7 days, etc.); and thereafter(2) topically applying to the same area of skin an effective amount(e.g., from about 0.001-5% by weight) of a retinoid (e.g., retinol)containing composition for a second period of time (e.g., 1-31 days, or3-20 days, or 5-10 days, or 7 days, etc.). The steps may be performed ineither order. Typically, the two periods of time end and begin onconsecutive days, such that there is not an intervening day withouttreatment. In some implementations, however, there may be apredetermined number of intervening days (e.g., one, two, three, etc.)between the two periods of treatment. The method may further compriserepeating steps (1) and (2) for one, two, three, four or more additionaltimes, ideally until an improvement in skin health and/or a reduction inthe dermatological signs of aging is noted. The method may be carriedout chronically or indefinitely for continued treatment and/orprophylaxis. In some implementations, the method is for reducing theappearance of wrinkles and/or fine lines, including reducing the numberof such wrinkles and/or fine lines, reducing the depth of such wrinklesand/or fine lines, or forestalling the development or, or progression ofsuch wrinkles and/or fine lines. In some implementations, the method isfor reducing unwanted pigmentation in the skin, including withoutlimitation, reducing age spots, freckles, sun spots, and the like, orfor reducing the mottled appearance of skin and/or evening skin tone.

In another aspect, a method for diminishing the appearance ofdermatological signs of aging (e.g., treating wrinkles and/or fine line,and/or treating skin sagging/improving elasticity and/or evening skintone and/or reducing unwanted pigmentation) is provided, comprising thesteps of: (1) topically applying to an area of skin in need therefore aneffective amount (e.g., from about 0.001-5% by weight) of aphytol-containing composition for a first period of time (e.g., e.g.,1-31 days, or 3-20 days, or 5-10 days, or 7 days, etc.); and topicallyapplying to the same area of skin an effective amount (e.g., from about0.001-5% by weight) of a retinol-containing composition for a secondperiod of time (e.g., e.g., 1-31 days, or 3-20 days, or 5-10 days, or 7days, etc.), and (3) repeating steps (1) and (2) for at least one (e.g.,two, three, four or more) additional times (or repeating until animprovement is noted). Steps (1) and (2) may be performed initially ineither order and repeated in that same order in step (3). The twoperiods of time may end and begin on consecutive days, such that thereis not an intervening day without treatment, or there may be apredetermined number of intervening days (e.g., one, two, three, etc.)between the two periods of treatment. The method may be carried out forat least one, two, four, eight, or twelve weeks or longer, until abenefit is seen, including chronic or indefinitely continued treatmentfor maintenance and/or prophylaxis.

In one aspect of the invention, a method for diminishing dermatologicalsigns of aging in human skin is provided comprising, in any order, thesteps of (1) topically applying to an area of the skin in need thereof(e.g., skin of the face, neck, chest, hands, etc.), at least once daily(e.g., once daily at night or in the morning), a first skin treatmentcomposition comprising, in a physiologically compatible vehicle (e.g.,an oil-in-water emulsion comprising from 0.01-10% by weight of anemulsifier), an effective amount (e.g., 0.01% to about 1% by weight) ofa retinoid (e.g., retinol) for a first period of time comprising from 1to 31 days (e.g., from 2-15 days, or for seven days); (2) implementing asecond treatment modality for a second period of time comprising from 1to 31 days (e.g., from 2-15 days, or for seven days); and (3) repeatingsteps (1) and (2) for a number of times (e.g., four or more) sufficientto diminish said dermatological signs of skin aging (e.g., treatwrinkles and/or fines lines and/or diminish appearance of unwantedpigmentation). In one implementation, the second treatment modalitycomprises topically applying to said same area of skin, at least oncedaily (e.g., once daily at night or in the morning), a second skintreatment composition that is different from said first skin treatmentcomposition (e.g., it does not comprise an effective amount of aretinoid such as retinol), and which may comprise, in a physiologicallycompatible vehicle (e.g., an oil-in-water emulsion comprising from0.01-10% by weight of an emulsifier), one or more skin active agents,including withtout limitation, α-hydroxy acids (e.g., glycolic acid,lactic acid, citric acid, etc.) and/or antioxidants (e.g., ascorbicacid, beta-carotene, hexylresorcinol, tocopherol and its derivatives,including acetate esters, phytol, phytanic acid, and thiodipropionicacid and its di-alkyl esters, including di-lauryl esters), such as, forexample, from about 0.01% to about 10% by weight phytol, from about0.01% to about 10% by weight glycolic acid, and/or from about 0.01% toabout 10% by weight thiodipropionic acid or esters (e.g., di-laurylesters) thereof. Typically, in the practice of the method according tothis embodiment, the first and second periods of time are consecutivesuch that one begins on the day following the last day of the other, andin one particular implementation, both the first and second periods oftime are seven days.

Typically, the method is repeated for a period of time sufficient toimprove the health of skin and/or achieve a desired benefit ofdiminishing the signs of aging in the skin (e.g., reduction in number orseverity of wrinkles and/or fine lines, reduced sagging/improvedelasticity, thicken thinning skin, and/or more even skin tone, and/orreducing unwanted pigmentation, etc.). This may entail topicalapplication at least once daily for at least one week, at least twoweeks, at least four weeks, or at least eight weeks or more. In someembodiments, the compositions are applied directly to a specific site ofthe skin (i.e., directly onto a wrinkle, directed to a hyperpigmentedspot, under the eyes, etc.). In some embodiments, the first and/orsecond compositions will be applied to the skin in an amount from about0.001 to about 100 mg/cm², more typically from about 0.01 to about 20mg/cm², or from about 0.1 to about 10 mg/cm².

In yet another aspect of the invention, a kit is provided comprising:(i) a first composition comprising a topically acceptable vehicle (e.g.,emulsion, gel, or serum) and an effective amount (e.g., from about0.001-5% by weight) of a retinoid (e.g., retinol or its esters, such asacetate, propionate, palmitate, etc., retinaldyhede, retinoic acid,etc.); and (ii) a second composition comprising a topically acceptablevehicle (e.g., emulsion, gel, or serum) and an effective amount (e.g.,from about 0.001-5% by weight) of a skin active, such as an antioxidant,alpha-hydroxy acid, botanical, etc., including, for example, phytoland/or TDPA (or its di-alkyl esters) and/or glycolic acid, and (iii)written instructions for topically applying said first and secondcompositions, in any order, in alternating fashion, such that the firstcomposition is applied at least once daily for a first period of timeand said second composition is applied at least once daily for a secondperiod of time. The instructions may further indicate that thealternating treatments are carried out without a gap in between them,such that one begins on the day following the end of the other, or mayprovide for a predetermined gap (e.g., one day, one week, etc.), betweenthe end of one treatment period and the beginning of the next. Theinstructions may indicate that the first period of time will be fromabout one day to about one month (or from 3-20 days or from 5-10 days or7 days) and the second period of time will be from about one day toabout one month (or from 3-20 days or from 5-10 days or 7 days). Theinstructions may also indicate that the compositions may be applied ineither order (e.g., first treatment period followed by second treatmentperiod, or, alternatively, second treatment period followed by firsttreatment period). The instructions may indicate that the treatments maybe repeated. The instructions may specify any number of alternatingtreatments (e.g., one, two, three, four, or more) with said first andsecond compositions. The instructions may indicate that the treatmentshould be carried out for long enough to achieve a visible improvementin the health and/or appearance of skin (e.g., a reduction in the numberand/or depth of wrinkle or fine lines, reduction in unwantedpigmentation, etc.). In some implementations, the instructions indicatethat the treatment is continued for at least 4 weeks, at least 8 weeks,at least 12 weeks, or more. The written instructions may be included onthe container, associated packaging, or on a website. In the case wherethe instructions are on a website, the container or packaging willcomprise written instructions for accessing the website (including, forexample, a QR code, etc.). The first and second compositions may bephysically separated from one another, for example, in separatecontainers, or within separate reservoirs within the same container. Thefirst and second compositions each may be provided in amountscorresponding to the same predetermined number of treatments (e.g.,equivalent number of doses). The first and second compositions each maybe contained in a plurality of containers corresponding to an individualdose. The first and second compositions each may be contained incontainers bearing written instructions for the period of use of eachcomposition. The first and/or second compositions may further include asunscreen.

In yet another aspect of the invention, a skincare product is providedcomprising a container comprising a first reservoir containing a firstskin treatment composition and a second reservoir containing a secondskin treatment composition, different from said first skin treatmentcomposition, a first pump in fluid communication with the firstreservoir for dispensing said first skin treatment composition, and asecond pump in fluid communication with the second reservoir fordispensing said second skin treatment composition, wherein each pumpoptionally is covered by a removable cap. The container may be in theshape of an elongate cylinder, having the first pump and second pumpdisposed on opposite ends thereof. The first and second reservoirs mayor may not be separable from one another. The container may comprise(e.g., on a visible surface thereof or on a label affixed thereto)visible identifiers for distinguishing the first and second reservoirs.In one embodiment, the identifiers may comprise alpha-numeric symbols(e.g., a number or letter identifying one reservoir/composition and adifferent number or letter identifying the other reservoir/composition).In another embodiment, the identifiers may comprise a visual identifier,such as different colors, patterns, artworks, pictures, etc. (e.g., onecolor identifying one reservoir/composition and a different coloridentifying the other reservoir/composition). Combinations oralpha-numeric identifiers and other visual identifiers may also be used.In another embodiment, the identifiers comprise a symbol other than analpha-numeric symbol. The product will typically include, either on thelabel, packaging, associated website, etc., written instructions fortopically applying to an area of skin in need thereof an amount of saidfirst skin treatment composition (e.g., at least once daily) for a firstperiod of time comprising from 1-31 or from 2-15 days or 7 days,followed by topically applying to said area of skin said second skintreatment composition (e.g., at least once daily) for a second period oftime comprising from 1-31 or from 2-15 days or 7 days). In someimplementations, the first composition may comprise a topicallyacceptable vehicle (e.g., an oil-in-water emulsion with 0.01-10% byweight of an emulsifier) and an effective amount (e.g., from about0.001-5% or 0.05-1% by weight) of a retinoid (e.g., retinol or itsesters, such as acetate, propionate, palmitate, etc., retinaldyhede,retinoic acid, etc.), typically retinol; and (ii) a second compositioncomprising a topically acceptable vehicle (e.g., an oil-in-wateremulsion with 0.01-10% by weight of an emulsifier) and an effectiveamount (e.g., from about 0.001-5% or 0.05-1% by weight) of a skinactive, such as an antioxidant, alpha-hydroxy acid, botanical, etc.,including, for example, phytol and/or TDPA (or its di-alkyl esters)and/or glycolic acid. The first and second skin treatment compositionsmay, for example, each have a viscosity between about 10,000 cps and250,000 cps (e.g., between 25,000 cps and 150,000 cps, or between 50,000and 100,000 cps when measured at a shear rate of 10 s⁻¹ at 25° C., andmay have a similar or distinct attribute selected from tactile feel,scent, color, or other visual attribute and/or the perception of coolingor heating. In some implementations, the viscosity of said secondcomposition is within ±50% or ±40% or ±30% or ±20% or ±10% or ±5% of theviscosity of said first composition. In some embodiments, the productwill include visible identifiers indicating each day of the week, forexample, printed on a label affixed to the container. For example, theproduct may have a label adhered to the container, and the label mayhave the letters such as “M T W TH F SA SU” printed thereon to identifyeach day of the week. The product may be provided with a sticker for theuser to place onto the appropriate day of the week label on which thetreatment regimen began, to serve as a reminder to alternate between thefirst and second treatment compositions every week on that particularday. In a related aspect, a system is provided comprising: the packagedskincare product and a server for sending notifications, over a network(e.g., a cellular, wireless, cable, internet, satellite, etc.),instructing a user of the packaged product as to which of said first orsecond skin treatment compositions to topically apply to said skin. Thenotifications may be sent daily or may be sent at least one day duringsaid first period of time, and at least one day during said secondperiod of time, for example, prior to the start of the next treatmentmodality. The server may also be configured to receive a start date forthe treatment regimen from the user's computer. The system may furthercomprise a user's computer (e.g., smartphone, etc.) remote from theserver for sending a start date to the server over a network, andreceiving notifications from the server over the network.

These and other aspects of the present invention will be betterunderstood by reference to the following detailed description andappended embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot of the amount of pro-collagen I as a function oftreatment time in skin cells treated with (i) phytol alone (▪), or (ii)retinol alone (▴) for 16 days. It is evident from FIG. 1 that retinoland phytol both plateau in effectiveness over time.

FIG. 2 is a plot of pro-collagen I production in cells treated with (i)phytol alone for 16 days, (ii) retinol alone for 16 days, (iii) retinolalone for 6 days followed by phytol alone for 10 days, (iv) phytol alonefor 6 days followed by retinol alone for 10 days, as well as (v)untreated control cells.

FIG. 3 is a sample calendar of one embodiment of the invention showing apossible rotational regimen.

FIG. 4 and FIG. 5 are examples of packaging embodiments of the presentinvention.

FIG. 6 is a flow chart of a method and system for notifying a user of aproduct according to the invention, which of two treatment compositionsshould be used on a particular day.

FIG. 7 and FIG. 8 are examples of another packaging embodiment of theinvention having two reservoirs in a single container which are notseparable from one another and which are each charged with a differentskincare composition.

FIG. 9-11 are cross sectional views of a packaging embodiment of theinvention illustrating operation of each pump to dispense a firstcosmetic composition from the first reservoir using the first pump (FIG.10) and dispensing a second cosmetic composition from a second reservoirusing the second pump (FIG. 11).

FIGS. 12A and 12B illustrate embodiments of the invention wherein twocompositions are contained in separate reservoirs in a single container,where the container is marked with an alpha-numeric symbol identifyingeach reservoir (in this case, “1” and “2”). FIG. 12A also has anidentifier indicating each day of the week visible on the container'sexterior. FIG. 12B illustrates a variant of the embodiment of FIG. 12Ain which a circular sticker has been placed on the day of the week onwhich the treatment regimen began (in this case, Monday or “M”). Thepackaging or label on the exterior of the container may have differentcolors or patterns or other visible images to identify reservoir 14 and16 as indicated in FIGS. 12A and 12B by the different hatch marks.

FIG. 13 is a plot of the percentage change from a control in the amountof hyaluronic acid produced in human dermal fibroblast when exposed to(A) a ten day treatment of hydroponic Tiliacora triandra extract, (B) aten day treatment of niacinamide, (A+B) a ten day treatment of Tiliacoratriandra and niacinamide, (B/A) a five day treatment of Tiliacoratriandra followed by a five day treatment of niacinamide, and (B/A) afive day treatment of niacinamide followed by a five day treatment ofTiliacora triandra. Columns marked with a “*” indicate statisticalsignificance.

FIG. 14 is a plot of the percentage change from a control in the amountof hyaluronic acid produced in human dermal fibroblast when exposed to(1) a ten day treatment of retinol (“A”), (2) a ten day treatment ofcoleus (“B”), (3) a ten day treatment of retinol and coleus (“A+B”), (4)a five day treatment of retinol followed by a five day treatment ofcoleus (“AM”), and (5) a five day treatment of coleus followed by a fiveday treatment of retinol (“B/A”). Columns marked with a “*” indicatestatistical significance.

FIG. 15 is a plot of the percentage change from a control in the amountof hyaluronic acid produced in human dermal fibroblast when exposed to(1) a ten day treatment of niacinamide (“A”), (2) a ten day treatment ofglycolic acid (“B”), (3) a ten day treatment of niacinamide and glycolicacid (“A+B”), (4) a five day treatment of niacinamide followed by a fiveday treatment of glycolic acid (“A/B”), and (5) a five day treatment ofglycolic acid followed by a five day treatment of niacinamide (“B/A”).Columns marked with a “*” indicate statistical significance.

FIG. 16 is a plot of the percentage change from a control in the amountof hyaluronic acid produced in human dermal fibroblast when exposed to(1) a ten day treatment of KTFK (“A”), (2) a ten day treatment ofhydroponic Tiliacora triandra extract (“B”), (3) a ten day treatment ofKTFK and Tiliacora triandra (“A+B”), (4) a five day treatment of KTFKfollowed by a five day treatment of Tiliacora triandra (“A/B”), and (5)a five day treatment of Tiliacora triandra followed by a five daytreatment of KTFK (“B/A”).

FIG. 17 is a plot of the percentage change from a control in the amountof hyaluronic acid produced in human dermal fibroblast when exposed to(1) a ten day treatment of glycolic acid (“A”), (2) a ten day treatmentof hydroponic Tiliacora triandra extract(“B”), (3) a ten day treatmentof glycolic acid and Tiliacora triandra (“A+B”), (4) a five daytreatment of Tiliacora triandra followed by a five day treatment ofglycolic acid (“A/B”), and (5) a five day treatment of glycolic acidfollowed by a five day treatment of Tiliacora triandra (“B/A”). Columnsmarked with a “*” indicate statistical significance.

FIG. 18 is a plot of the percentage change from a control in the amountof hyaluronic acid produced in full thickness 3D models when exposed to(1) a ten day treatment of glycolic acid (“A”), (2) a ten day treatmentof hydropnic Tiliacora triandra extract (“B”), (3) a ten day treatmentof glycolic acid and Tiliacora triandra (“A+B”), (4) a five daytreatment of glycolic acid followed by a five day treatment of Tiliacoratriandra (“A/B”), and (5) a five day treatment of glycolic acid followedby a five day treatment of Tiliacora triandra (“B/A”). Columns markedwith a “*” indicate statistical significance.

FIG. 19 is a plot of the percentage change from a control in the amountof pro-collagen type I produced in human dermal fibroblasts when exposedto (1) a ten day treatment of retinol (“A”), (2) a ten day treatment ofColeus forskohlii (“B”), (3) a ten day treatment of retinol and Coleusforskohlii (“A+B”), and (4) a five day treatment of Coleus forskohliifollowed by a five day treatment of retinol (“B/A”). The column markedwith a “*” indicate statistical significance.

FIG. 20 is a plot of the percentage change from a control in the amountof pro-collagen type I produced in human dermal fibroblasts when exposedto (1) a ten day treatment of phytol (“A”), (2) a ten day treatment ofretinol (“B”), (3) a five day treatment of phytol followed by a five daytreatment of retinol (“A/B”), and (4) a five day treatment of retinolfollowed by a five day treatment of phytol (“B/A”). The columns markedwith a “*” indicate statistical significance.

DETAILED DESCRIPTION OF THE INVENTION

Detailed embodiments of the present invention are disclosed herein;however, it is to be understood that the disclosed embodiments aremerely illustrative of the invention that may be embodied in variousforms. In addition, each of the examples given in connection with thevarious embodiments of the invention is intended to be illustrative, andnot restrictive. Therefore, specific structural and functional detailsdisclosed herein are not to be interpreted as limiting, but merely as arepresentative basis for teaching one skilled in the art to variouslyemploy the present invention.

All percentages given herein refer to the weight percentages of aparticular component relative to the entire composition, including thevehicle, unless otherwise indicated. It will be understood that the sumof all weight % of individual components within a composition will notexceed 100%. Unless otherwise indicated, any ingredient (includingactive and inactive ingredients) may be included in a composition in anamount from about 0.0001-50% or from 0.001-20% or from 0.01-10% or from0.1-5% by weight of the composition.

All terms used herein are intended to have their ordinary meaning unlessotherwise provided. The phrase “physiologically acceptable” or“physiologically compatible” is used interchangeably with “cosmeticallyacceptable,” “topically acceptable” and “dermatologically acceptable”and is intended to mean that a particular component is generallyregarding as safe and non-toxic for application to a human integument(e.g., skin) at the levels employed.

The term “prevent,” as used herein, includes delaying or slowing theonset of or progression of a particular sign of skin aging.

The phrase “individual in need thereof” refers to a human that couldbenefit from improved dermal appearance or health, including males orfemales. In some embodiments, the individual in need thereof is afemale.

The term “skin” includes, without limitation, the lips, skin of theface, hands, arms, neck, scalp, and chest. As used herein, the term“consisting essentially of” is intended to limit the invention to thespecified materials or steps and those that do not materially affect thebasic and novel characteristics of the claimed invention, as understoodfrom a reading of this specification.

The identification of a particular active agent as having a certainactivity is not limiting, unless otherwise indicated, and does notpreclude the same agent from having additional activities. For example,TDPA is listed herein as an “antioxidant,” but it is also known to be apotent skin lightening agent. Likewise, hexylresorcinol also isidentified herein as an “antioxidant,” but it is also known to haveantimicrobial, antiseptic and anesthetic activity, and is contemplatedto be a skin lightening agent.

Reference to “C₂₋₂₀ esters” of active agents will be understood toinclude esters formed by C₂₋₂₀ hydrocarbon alcohols with carboxylic acidgroups on the subject active agents or esters formed by C₂₋₂₀hydrocarbon carboxylic acids with alcohol groups on the subject activeagents. Likewise, “C₂₋₂₀ amides” of active agents will be understood toinclude amides formed by C₂₋₂₀ hydrocarbon amines with carboxylic acidgroups on the subject active agents or amides formed by C₂₋₂₀hydrocarbon carboxylic acids with amine groups on the subject activeagents. The C₂₋₂₀ esters and amides, include, without limitation C₂₋₆esters and amides, C₇₋₁₁ esters and amides, and C₁₂₋₂₀ esters andamides. The hydrocarbons may be aliphatic, aromatic, or partly aromaticand aliphatic. The hydrocarbons may be saturated, or contain one or moreunsaturated (e.g., olefinic) bonds. In some embodiments, the C₂₋₂₀esters or amides may be acetyl, propyl, lauryl, palmitate, palmitoyl,etc. In some embodiments, the “C₂₋₂₀ esters or amides” comprise astraight chain aliphatic C₁₆ hydrocarbon. The present invention embracesthe use of all C₂₋₂₀ esters of all active agents described herein thathave derivatizable hydroxyl or carboxylic acid functionalities. Theinvention also embraces the use of all C₂₋₂₀ amides of all active agentsdescribed herein that have derivatizable (i.e., reactive) amino orcarboxylic acid functionalities.

The invention also embraces physiologically acceptable salts (e.g., acidaddition salts, carboxylate salts, etc.) of any of the activesidentified herein. The salts of the compounds that may be used accordingto the invention may be chosen from alkali metal or alkaline-earth metalsalts or from zinc, magnesium or strontium salts, salts of an organicamine or quaternary ammonium salts. The salts of the compounds inaccordance with the invention may be chosen from the salts of a mineralor organic acid, especially the hydrochlorides, hydrobromides orcitrates.

In some embodiments of the present invention, at least two separatecompositions are provided, each differing with respect to the identityor amount of at least one active ingredient. The active agent (“skincareactive”) will typically be dispersed or dissolved in a physiologicallyacceptable carrier (or diluent or vehicle). In various embodiments, anyof the topical compositions of the invention (including the first and/orsecond, etc.) may comprise an effective amount of one of the following:

Retinoids, including Retinol and its C₂₋₃₆ esters (e.g., acetate,palmitate);

Ascorbic acid and its salts and C₂₋₃₆ esters (e.g., palmitate,tetrahexyldecyl, etc.)

Tocopherol and its C₂₋₃₆ esters (e.g., tocopherol acetate);

Glycolic acid and its salts (e.g., sodium or ammonium glycolate) orC₂₋₃₆ esters;

Lactic acid and its salts (sodium or ammonium lactate) or C₂₋₃₆ esters(e.g., myristyl);

Hexylrescorcinol;

Niacinamide;

Thiodipropionic acid and its salts and C₂₋₃₆ esters (e.g., mono- anddi-lauryl);

Phytol and its C₂₋₃₆ esters;

Peptides (e.g., hydrolyzed wheat gluten, hydrolyzed rice protein,Tetrapeptide-4, etc.)

Palmitoyl oligopeptides (e.g., Palmitoyl Tetrapeptides, PalmitoylPentapeptides, etc.)

Palmitoyl lysyl aminovaleroyl lysine (KavaK);

Ceramides (e.g., Ceramide-2);

L-4-Thiazolylalanine;

Cis-6-nonenol;

N-Acetyl amino acids (e.g., N-Acetyl Tyrosinamide);

Mesyloxybenzyl isobutylbenzenesulfonamide;

Cinnamido benzylpiperidinyl ethoxypropylbenzamide;

Caffeine;

Hyaluronic Acid and salts (e.g., Sodium Hyaluronate) and

Salicylic acid and derivatives (e.g., C₂₋₃₆ esters) thereof.

In some embodiments, the any of the compositions of the invention (e.g.,the first, second, etc.) may comprise one or more of: AcetylHexapeptide-3, Acetyl Trifluoromethylphenyl Valyl-Glycine, AcetylTyrosinamide, Adenosine, Allantoin, All-Trans Retinoic Acid, AlphaLipoic Acid, Alpha-Isomethyl Ionone, Amino Acids (Arginine, Glutamate,Glycine, Lysine, Etc.), Ammonium Glycolate, Apigenin, Arabinogalactan,Ascorbic Acid, Ascorbyl Glucoside, Ascorbyl Palmitate, Aspartic Acid,Astaxanthin, Atelocollagen, Azulene, Beta-Glucans, Bio-Flavonoids,Biosaccharide Gum-1, Biotin, Butylphenyl Methylpropional, Caffeine,Calcium Pantetheine Sulfonate, Calcium Pantothenate, Carnitine,Carnosine, Ceramide-2, Chlorphenesin, Cinnamido BenzylpiperidinylEthoxypropylbenzamide, Cis-6-Nonenol, Citral, Citronellol, ColloidalPlatinum, Copper Peptides, Coumarin, Daidzein, DHT (Dihydrotestosteroneor 5α-Dihydrotestosterone), Dilauryl Thiodipropionate,Dimethylethanolamine (DMEA), Disodium Stearoyl Glutamate,Dithiolane-3-Pentanic Acid, Ellagic Acid, Eugenol, Farnesyl Acetate,Ferrulic Acid and Derivatives (Ethyl Ferrulate, Sodium Ferrulate, etc.),Finasteride, Galactoarabinan, Gamma-Amino Butyric Acid (GABA),Genistein, Geraniol, Glucosamine, Glutamine, Glutathione, Glycine SojaOil, Glycolic Acid, Hexamidine, Hexapeptide-2, Hexylrescorcinol, HGHReleasers, Hyaluronic Acid (HA) and salts, Hydrolyzed Rice Protein,Hydrolyzed Soy Protein, Hydrolyzed Wheat Gluten, Hydrolyzed WheatProtein, Hydroquinone, Hydroxyethylpiperazine Ethane Sulfonic Acid,Hydroxyisohexyl 3-Cyclohexene Carboxaldehyde,6-Hydroxy-2,5,7,Tetramethylchroman-2-Carboxylic Acid, Idebenone,Isoeugenol, Latanoprost, Limonene, Linalool, Lysine CarboxymethylCisteinate, Tetrapeptides (e.g., Lys-Thr-Phe-Lys), Lysyl AminovaleroylLysine, Magnesium Ascorbyl Phosphate, Malachite (antioxidant extract),Mesyloxybenzyl Isobutylbenzenesulfonamide, Minoxidil,N-Hydroxysuccinimide, Niacinamide, Nonenol, Oryzanol,Oxothiazolidinecarboxylic Acid, Palmitoyl Lysyl Aminovaleroyl Lysine(Kayak), Palmitoyl Oligopeptide, Palmitoyl Pentapeptide (Matrixyl),Palmitoyl Pentapeptide-3, Palmitoyl Pentapeptide-4, PalmitoylTetrapeptide, Palmitoyl Tetrapeptide-7, Palmitoyl Tetrapeptide-10,Panthenol, Panthetine Triacetate, Pentaerythrityl tetra-di-t-ButylHydroxyhydrocinnamate, Phloretin, Phytol, Phytosterols, Pichia PeptoneFiltrate, Polyphenol Antixoidants, Propolis, Pycnogenol, PyridoxineHydrochloride, Quercetin, Resveratrol, Retinaldehyde, Retinoic Acid,Retinol, Retinyl Palmitate, Royal Jelly, Rutin, Saccharide Isomerate,Salicylic Acid, Salicyloyl Phytosphingosine, Sodium Chondroitin Sulfate,Sodium Hyaluronate, Soil Minerals, Sphingolipids, Sphingosine, SugarAmines, Superoxide Dismutase, Tetrahexydecyl Ascorbate, Tretrapeptide-4,Thiazolylalanine, Thiodipropionic Acid, Tocopherol, Tocopheryl Acetate,Tretinoin, Trioxaundecanedioic Acid, Ubiquinone (Co Q10), Vitamin A,Vitamin B3, Vitamin E (Tocopherol), Xymenynic Acid, Zinc, and ZincPyrithione.

In some embodiments, one composition comprises a C₂₀-C₂₅ terpene alcohol(e.g., phytol) or a metalobilte thereof formed in human tissues (e.g.,phytanic acid). In some embodiments, one composition comprises aretinoid (e.g., vitamin A, retinol, retinyl acetate, retinyl,propionate, reintyl palmitate, rentin-A, retinoic acid, retinaldyhyde,etc.).

In some embodiments, the first and second compositions will differ withrespect to the presence of or amount of at least one active component.In some embodiments, however, the first and second compositions maycomprise the same amount of an active agent, provided there are otherdifferences between them (e.g., differences in the identity or amount ofanother active agent.

In some embodiments, at least one composition (e.g., the firstcomposition) may comprise retinol (or an ester), and the secondcomposition may either be free or essentially free of retinol (or anester), by which is mean it comprises less than an effective amount, orcomprise an amount of retinol (or an ester) that is more or less thanthe amount contained in the first composition.

The two different compositions form the bases of two different treatmentmodalities, each being carried out for a limited period of time,typically a predetermined period of time, after which the othertreatment is carried out for a limited, typically predetermined, periodof time. This process can be repeated any number of times to improve thehealth and appearance of human skin, while ideally overcoming ordiminishing the impact of the sensitization or tolerance phenomenon thatdevelops with skincare active, including retinoids and/or phytoltreatment. The process may also be implemented with three, four, five,six, or seven (or more) different compositions in a like manner.

Without wishing to be bound by any theory, it is believed that methodsaccording to some embodiments of the present invention provide multipleskin care benefits by activating retinoid X receptors (RXRs), peroxisomeproliferator activated receptor (PPAR), and/or retinoic acid receptorsRARs. Activating these receptors and responsive genes stimulates cellfunctions in multiple components of skin, such as the epidermis, dermis,sebaceous glands, melanocytes, Langerhan cells, and hair follicles whilethe alternating application allows skin resensitization. In someembodiments, the active agents, including a retinoid (e.g., retinol) anda C₂₀-C₂₅ terpene alcohol (e.g., phytol) or a metalobilte thereof formedin human tissues (e.g., phytanic acid), share at least one commonmechanism of action, including, without limitation, activity at RXRs,PPARs, and/or RARs.

Phytol and its derivatives (e.g., C₁₋₂₀ ethers and esters) belong to theclass of compounds which can be referred to as C₂₀-C₂₅ terpene alcohols.The phytol derivatives of the invention may comply with the structuralformulas provided in WO 2001/066080 and U.S. Pat. No. 7,960,437, thedisclosures of which is hereby incorporated by reference. Phytanic acidis also contemplated to be a useful phtyol derivative. Suitable phytolderivatives include, without limitation, C₁₋₂₀ hydrocarbon esters fromthe esterification of phytol with a C₁₋₂₀ carboxylic acid, or C₁₋₂₀hydrocarbon esters from the esterification of phytanic acid with a C₁₋₂₀hydrocarbon alcohol. The invention encompasses the use of phytol, aswell as phytol derivatives (esters, ethers, etc.), phytol precursors,and phytol metabolites (including phytanic acid). Metabolic precursorsof phytol are compounds from which phytol can be formed by action ofenzymes present in human tissues, particularly skin. Metabolites ofphytol are compounds formed by action of enzymes present in humantissues, particularly skin, on phytol.

In some embodiments, a composition of the present invention willcomprise phytol, for example in an amount about 0.001 percent by weight(wt %) to about 10 wt % based on the total weight of the composition.Typically, phytol may be present in an amount about 0.01 wt % to about 5wt %, and most typically about 0.1 wt % to about 1 wt %, based on thetotal weight of the composition.

The term “retinoid” includes: (1) retinol; (2) esters of retinol withcarboxylic acids of 1 to 24 carbon atoms, such as retinyl acetate,retinyl propionate, retinyl butyrate, retinyl octanoate, retinyllaurate, retinyl palmitate, retinyl oleate, retinyl linoleate, and thelike; (3) esters of retinol having an alpha-hydroxy carboxylic acid; (4)ether derivatives of retinol, including C₁₋₂₄ alkyl ether, ethersderived from glycolic acid, as well as glycolate ester and amide, suchas retinyl glycolyl ether; (5) retinaldehyde; (6) retinoic acid; (7)esters of retinoic acid with alcohols of 1 to 24 carbon atoms; (8)isotretinoin as well as synthetic retinoid mimics, and derivatives ofthe foregoing, as well as others that bind to RAR receptors; (9) cis-and trans-isomers of the foregoing retinoids; (10) salts of theforegoing retinoids; and (11) mixtures of the any of the foregoingcompounds. A preferred retinoid for use in a composition according tothe present invention is retinol, including the cis- or trans-isomer ofretinol, typically the trans isomer.

In some embodiments, a composition of the invention may comprise aretinoid (e.g., retinol) in an amount about 0.001 wt % to about 10 wt %based on the total weight of the composition. Typically, the retinoid(e.g., retinol) is present in an amount about 0.01 wt % to about 5 wt %,or about 0.1 wt % to about 2.5 wt %, based on the total weight of thecomposition. The amount of retinoid may be adjusted, based upon thepotency of the retinoid, without departing from the present invention.

The invention provides methods that improve and/or support the health ofskin and/or improve the appearance of one or more signs ofdermatological aging when topically applied to human integuments (skin,lips, nails, hair, etc.), particularly skin, such as skin of the face.In some embodiments, at least two separate compositions, in which onecomposition has an antioxidant, such as a C₂₀-C₂₅ terpene alcohol (e.g.,phytol), and the other composition has a different skincare active, suchas a retinoid (e.g., retinol), are topically applied to the same area ofskin in a sequential, rotating, or alternating fashion.

The two or more treatment modalities will typically comprise: (1)topical application (typically, at least once daily) of a firstcomposition comprising a first active ingredient for a first period oftime, and (2) topical application (typically, at least once daily) of asecond composition comprising a second active ingredient for a secondperiod of time, and (3) optionally repeating steps (1) and (2) one ormore times. The first and second compositions may comprise at least oneactive ingredient that is different from the other, or is present in adifferent amount. In some embodiments, the first composition comprisesphytol. In some embodiments, the second composition comprises phytol. Insome embodiments, the first composition comprises retinol. In someembodiments, the second composition comprises retinol. In someembodiments, the first composition comprises phytol and the secondcomposition does not comprise phytol or comprises phytol in a lesseramount than the first composition. In some embodiments, the firstcomposition comprises retinol and the second composition does notcomprise retinol or comprises retinol in a lesser amount than the firstcomposition. In some embodiments, the second composition comprisesphytol and the first composition does not comprise phytol or comprisesphytol in a lesser amount than the second composition. In someembodiments, the second composition comprises retinol and the firstcomposition does not comprise retinol or comprises retinol in a lesseramount than the second composition.

In some embodiments, the first composition is topically applied to theskin, at least once daily (e.g., once, twice or thrice daily, etc.) fora period of time from about 1-31 days (or from 1-5 days), or from about3-20 days, or from about 5-10 days, or for about one week. In someembodiments, the second composition is topically applied to the samearea of skin, at least once daily (e.g., once, twice or thrice daily,etc.) for a period of time from about 1-31 days (or from 1-5 days), orfrom about 3-20 days, or from about 5-10 days, or for about one week. Insome embodiments, treatment with the second composition will begin aftera predetermined time following the end of the first period of time,including, on the following day, or after two, three or more days (e.g.,after five days, or one week), during which time the individual mayoptionally receive no treatment or may receive a treatment other thanwith the first and second compositions. In some embodiments, treatmentwith the first composition will begin after a predetermined timefollowing the end of the second period of time, including, one thefollowing day, or after two, three or more days (e.g., after one week),during which time the individual may optionally receive no treatment ormay receive a treatment other than with the first and secondcompositions. In some embodiments, treatment with the second compositionwill begin on the day following the end of the first period of time. Insome embodiments, treatment with the first composition will begin on theday following the end of the second period of time. In variousembodiments, the treatment protocol will comprise the following: AB,ABA, ABAB, ABABA, or ABABAB, etc. In various embodiments, the treatmentprotocol will comprise the following: BA, BAB, BABA, BABAB, BABABA,etc., where “A” represents the first treatment period with the firstcomposition and “B” represents the second treatment period with thesecond composition. The treatments may be continued until a skin benefitis observed or longer. The treatment protocol may be represented as(AB)_(n+1) or (BA)_(n+1), where “n” is an integer indicating the numberof times the method is repeated. For example, “n” may be 1, 2, 3, and soon, up to 100 or more. Referring now to FIG. 3, a schedule for apossible first treatment period “A” and a second treatment period “B” isshown. In this embodiment, treatment period “A” is 7 days long andtreatment period “B” is 7 days long. In another embodiment, treatmentperiod “A” is 5 days long and treatment period “B” is 2 days long.

In some embodiments of the invention, a third treatment modality, suchas topical application of a composition comprising an active agentdifferent from said first and second compositions, may also be employedin sequence with the first and second treatment modalities. The thirdcomposition may be applied at least once daily for a third period oftime according to the criteria described above. In various embodiments,the treatment protocol will comprises the following: ABC, ABCA, ABCAB,ABCABC, etc. and all permutations thereof, where “A” represents thefirst treatment period with the first treatment modality, “B” representsthe second treatment period with the second treatment modality, and “C”represents the third treatment protocol with the third treatmentmodality. There is essentially no limit to the number of treatmentmodalities that may be employed, or the combination/permutation oforders in which these treatment modalities are employed. For example,the treatment may comprise two, three, four, five, six, seven or moredifferent treatments, where each is typically employed at least once perday for a period from 1-31 days.

In some embodiments, any of the compositions of the invention maycomprise any active for treating human skin. In some embodiments, anycomposition of the invention may be free of any active for treatinghuman skin that is present in another of the compositions of theinvention. In some embodiments, any of the compositions may include (ormay be free of) an active ingredient selected from glycolic acid (andsalts thereof), thiodipropionic acid (TDPA) or esters thereof (e.g.,mono- and di-lauryl alcohol esters), hexylrecorcinol, niacinamide, or abotanical extract from a plants of the genus Eclipta (e.g., Ecliptaprostrata), Portulaca (e.g., Portulaca grandiflora), Tiliacora (e.g.,Tiliacora triandra) or Melicope (e.g., Melicope hayesii and/or Melicopeellyarana), etc. In some embodiments, the active ingredient willactivate retinoid X receptors (RXRs), peroxisome proliferator activatedreceptor (PPAR), and/or retinoic acid receptors RARs. In someembodiments, the active ingredient will not activate retinoid Xreceptors (RXRs), peroxisome proliferator activated receptor (PPAR),and/or retinoic acid receptors RARs.

In some embodiments, the compositions of the invention (e.g., the firstand/or second compositions, etc.) will comprise a biological extract.The extract may be an extract of a plant, yeast, fungus, etc. Theextract may be from the roots and/or arial portions of a plant,including, without limitation, the stems, branches, bark, leaves,flowers, seeds, roots, fruit, rhizomes, vines, etc. Other biologicalmaterials, such as honeys may also be useful. Extracts include ground orpulverized plant materials, as well as ferments, lysates, and isolates.Without limiting the invention, extracts from the following arecontemplated to be useful:

Abies pindrow, Abrus fruticulosus, Abutilon indicum, Acai, Acaciacatechu, Acacia dealbata, Acacia melanoxylon, Acer Saccharinum, AcerSaccharum (Sugar Maple), acidopholus, aesculus, Aesculus hippocastanum(horse chestnut) seed, Aframomum melegueata, agaricus, agave, agrimonia,algae, Alisma orientale, Allamanda cathartica, almond, aloe, Aloebarbadensis leaf juice, Alpinia galanga leaf Amomum melegueta,Amorphophallus campanulatus (rhizome/root), Ananas sativus (pineapple)fruit, Anogeissus latifolia, Anthemis nobilis (flower), Antidesma bunis,Apple extract, Apricot kernel, Aradirachta indica, Archidendronclypearia, Arctostaphylos viscida, Argania spinosa, Argania spinosakernel, Aribodopsis Thaliana, Arnica flower, Ascophyllum Nodosum,Asmunda japonica, Asparagopsis, Atriplex portulacoides, Averrhoacarambola, Azadirachta indica (Neem), Basella alba, bearberry, bearberryextract, Berchemia lineata (leaf), Beta vulgaris, Bifida Ferment lysate,birch bark extract, Bitter orange flower, black cohosh (Cimicifugaracemosa), Black honey, Black Tea Ferment, Boswellia serrata, brassica,Brassica Napus, Breynia fruticosa, Bupleurum falcatum root, Buteafrondosa, Butea monosperma, Butyrospermum Parkii Butter, Caesalpiniasappan Linn, Calatropis gigantean, Calendula officinalis, Callistephuschinensis, Calotropis gigantea, Camelina sativa, Camellia oleifera leaf,Camellia sinensis leaf, Cananga odorata, Capsicum amuum, Capsicumfrutescens oleoresin, Carica papaya (papaya) fruit, Carrot, cashew,Castanea sativa, Cayratia japonica, cedar, Cedrelopsis grevei, Cedrusdeodara, Celosia argentea, Centella asiatica, Ceratonia siliqua (carob),Cereus grandiflorus (cactus) flower, Chalara microspora, chamomile,Chamomilla recutita (matricaria) flower, Chestnut seed, Chlorellavulgaris, Chondrus crispus, Cimicifuga racemosa root, cinnamon,Cistanche tubulosa, Cistus ladaniferus L., Citronella, Citrus aurantium,Citrus aurantium dulcis (Orange) Fruit, Citrus aurantium dulcis peel,Citrus Limon (Lemon) Fruit, Citrus Medica Limonum, Citrus ReticulataPeel, Clerodendron fragrans, Clerodendron lindleyi, Clerodendrumfloribundum, Clinacanthus nutans, Clintonia borealis, Clitoria ternateaLinn extract, Clove flower, Coccinia grandis, Cocculus glaucescens,Cocos nucifera (coconut) fruit juice, Coffea arabica (coffee) seed,cola, Cola nitida seed, comfrey, Coleus forskohlii, Commersoniabartramia, Commiphom, Copernicia cerifera cera, Corallina officinalis,Crataegus monogyna fruit, Crithmum maritimum, crocus flower, Cucumberfruit, Cucumis sativus (cucumber) fruit, Curcuma longa, CurcumaXanthorrhiza, Cymbopogon flexuosus, Cymbopogon nardus, Daucus carotasativa (carrot) root, Dendranthema indicum, Derris scandens, Desmanthusillinoensis, Dianella ensifolia, Dodonaea petiolaris, Dodonaea viscosa,Duboisa myoporoides, Eclipta prostrata, Edelweiss, Ehretia acuminate,Emblica officinalis, English lavender, Eperua falcata bark, Equisetumarvense, Equisetum Arvense (Horsetail), Eremophila mitchelli, Erthrinaflabelliformis, Erythina indica, Erythrina flabelliformis, Erythrinaindica, Eugenia caryophyllus flower, Eurya groffii, Evening primroseoil, Evernia furfuracea, Evernia prunastri, Eysenhardtia polistachya(Palo Azul) wood, Fagus sylvatica, fenugreek seed, Fibraretinum resicaPierre, Ficus benghalensis, Ficus coronata, fir needle (Abies alba),Foeniculum vulgare (fennel) fruit, forskohlii, Fructus Mume, Geranium,Ginkgo biloba, Glochidium wallichianum, Glycine soja (soybean),Glycyrrhiza glabra, Gomphrena globosa Linn, Goodenia ovata, Gracilariatextorii, green tea, Grifola frondosa, Gymnostemma pentaphyllum,Gynandropsis gynandra, Haberlea rhodopensis, Hamamelis viginiana,hawthorns, Hedyotis hedyotidea, Helianthus Annuus, Helianthus annuus(sunflower) seed, Helichrysum gymnocephalum, Helichrysum odoratissimum,Heliotropium indicum, hibiscus flower, Hibiscus sabdriffa, holly (Ilex),honey, Hordeum vulgare, Hoya carnosa, Humulus japonicus, HumulusLupulus, Humulus scandens, Hydrolyzed hibiscus esculentus, Hydrolyzedulva lactuca, Hymenosporum flavum, Hypericum performatum, Ilexparaguariensis leaf, Ilex purpurea Hassk, Innula racemosa, Ixorachinensis, Japanese knotweed, Jasminum officinale, Jasminum sambacextract, Jojoba seed, Jugans regia, Juniperus oxycedrus, Justiciaventricosa, Kunzea ambigua, laurel clock vine (Thunbergia laurifloria),Lavandin, Lavandula angustifolia (Lavender), Lavandula hybrida, Lavateraplebeian, Lavender, Lens esculenta seed, Lentinus edodes, Leptospermumlanigerum, Licorice, Ligusticum chiangxiong, Ligusticum lucidum,locorice, Lonchocarpus capassa, Loropetalum chinense, Lycium barbarium(tibetan wolfberry), Macrocycstis pyrifera, Maesa japonica, Mallotusphilippinensis, Malus domestica fruit cell culture, Mammea siamensis,Manuka Honey, Marjoram (leaf), Matricarria (flower), Medemia nobilis,Medicago sativa (alfalfa), Melaleuca quinquernervia, Melicope hayesii,Melicpoe ellyarana, Melissa officinalis, Melissa officinalis (leaf),Menyanthes trifoliata, Mimosa tenuiflora bark, Mimusops elengi, Morindacitrifolia, Moringa oleifera, Moringa pterygosperma, Morus Nigra, mucormiehei mushroom, MycoFusions Coriolus Black Corn Biomass, MycoFusionsMaitake Waxy Hulless Barley Biomass, Narcissus tarzetta, Naringicrenulata, Nerium indicum, Nigella sativa (seed), Norway spruce,Oenothera biennis oil, Olea europaea (olive) (leaf), Olisma orientaleextract, olive, Omolanthes populifolius, Operculina turpethum,Ophiopogon Thunb. P.E., Orange peel, Origanum heracleoticum flower,Origanum majorana (leaf), Orthosiphon grandiflorus, Oryza (rice) sativa,Ozothamnus obcordatus, Padina pavonica, palm nut, Palmaria palmata,Panax ginseng root, Pancratium maritimum, Passiflora edulis (seed),Passiflora incarnata flower, pecan, Pelargonium graveolens flower,Pelvetia canaliculata, Perilla, Perilla ocymoides (seed) oil,Phaeodactylum tricornutum, Phyllanthus acidus, Phyllanthus emblicafruit, Phyllarthron bojeranum, Physalis minima, pine needles, Piperbetel, Piper nigrum, Pisum sativum (Pea), plankton, Plumbago indica,Plumeria acuminata, Polyanthes tuberosa, Polygonum Cuspidatum,Pomegranate, Populus nigra, Portulaca oleracea, Portulaca sativa,Pouzolzia pentandra, Prunus amygdalus dulcis (sweet almond) seed, Prunusarmeniaca (kernel), Psoralea corylifolia, Pteris semipinnata, Puerarialobata symbiosome, Punica granatum fruit, Pygeum (Prunus) africanum,Pyrus malus, Pyrus malus (apple) root, Radix platycodonis, Raphiafarinifera, Rhinacanthus nasutus, Rhizophora mangle Bark, Rice bran oil,Roman chamomile, Rosa canina fruit, Rose flower, Rosemary (leaf),Rosmarinus officinalis, Royal jelly, Rubis, Rubus ideas (rasberryextract), Rumex crispus, Saccharomyces cerevisiae, Saccharum officinarum(Sugar Cane), Salix nigra, Salvia officinalis, Salvia Sclarea, Sambucuschinensis, Sapindus rarak (fruit), Sargassum muticum, Sativa bran oil,Saxifraga sarmentosa, Scenedesmus, Scoparis dulcis, Scutellariabaicalensis root, Sea Buckthorn, Sedum sarmentosum bunge, Seewead,Selaginella tamariscina, Serrisa japonica, Sesbania aculeata, Sesbaniagrandiflora (flower), Siegesbeckia orientalis, silver birch barkextract, Silybum marianum (fruit), Simmondsia chinensis, Sophoratomentosa, spruce needles, Stellaria medica (L.) cry., Stenolomachusana, Stephania rotunda, Stephania solid, Sunflower seed, Symphytumofficinale, Tagetes erecta Linn, Terminalia bellerica, Tetraceraasiatica, Theobroma cacao, Thermus thermophillus ferment, Thermusthermophilus, Thuja, Thunbergia laurifolia, Tilia cordata wood, Tiliaplatyphyllos, Tiliacora triandra, tomato glycolipid, Trifolium hybridum,Triticum vulgare (wheat) germ, Turmeric root, Uncaria gambir, Vacciniummacrocarpon (Cranberry), Vaccinium myrtillus Fruit/Leaf Vernoniacinerea, Vigna aconitifolia, Vitis vinifera (grape) fruit, Voandzeiasubsterranea, walnut, Water Lily, Willow (bark), Withania somniferia,yohimbine, Zanthoxylum nitidium, Zea mays (corn) kernel, and Zingibercassumunar Roxb.

In the above list of biological/botanical extracts, the part of theplant indicated in parentheticals or otherwise represents a non-limitingembodiment. It will be understood that the invention encompassesextracts from any portion of the forgoing plants and organisms. Inaddition, the particular species indicated are also merelyrepresentative of certain embodiments, and in each instance theinvention embraces extracts from any species within the genus. In otherwords, disclosure of Melicope hayesii, for example, will be understoodto include extracts from the species Melicope hayesii, as well asextracts from any species within the genus Melicope.

The extracts may be prepared by solvent extraction, steam distillation,or any other method known in the art. In some embodiments, at least oneof the topical compositions of the invention comprises an extract,obtained by steam distillation, of any of the forgoing plants andbiological materials (each one being considered a distinct embodiment).In some embodiments, at least one of the topical compositions of theinvention comprises an extract, obtained by extraction with water (e.g.,basic, neutral, or acid), of any of the forgoing plants and biologicalmaterials (each one being considered a distinct embodiment). The waterof extraction may further include a co-solvent miscible with water,including lower alcohols (e.g., C1-6), such as methanol, ethanol,isopropanol, propanol, butanol, etc. (typically, ethanol). In someembodiments, at least one of the topical compositions of the inventioncomprises an extract, obtained by extraction with a solvent systemcomprising from about 5-95% (v/v) or 10-90% (v/v) or 20-80% (v/v) or40-60% (v/v) water (e.g., basic, neutral, or acid) and about 5-95% (v/v)or 10-90% (v/v) or 20-80% (v/v) or 40-60% (v/v) ethanol, of any of theforgoing plants and biological materials (each one being considered adistinct embodiment). In some embodiments, at least one of the topicalcompositions of the invention comprises an extract, obtained byextraction with an organic solvent (e.g., non-polar, polar aprotic, orpolar protic), of any of the forgoing plants and biological materials(each one being considered a distinct embodiment). Suitable solventsinclude hexane and other C₁₋₁₂ or C₅₋₈ hydrocarbons, lower alcohols,C₂₋₁₆ ethers (e.g., diethyl ether), C₃₋₁₂ esters (e.g., ethyl acetate),C₂₋₁₂ (e.g., acetone, butanone, etc.), carbon dioxide (liquid orsupercritical), etc. The biological extracts may be dried under vacuumor atmospheric pressure to remove water and solvents of extraction. Thebiological extracts may be dried by lyophilization. The biologicalextracts may be passed over activated carbon or charcoal and/or passedthrough filters and/or microfilters to remove bacteria and otherbiological materials.

Typically, the treatment regimen of the invention is repeated for aperiod of time sufficient to improve the health of skin and/or achieve adesired benefit of diminishing the signs of aging in the skin (e.g.,reduction in number or severity of wrinkles and/or fine lines, orimproving elasticity and/or diminishing sagging, etc.). This may entailtreatment (e.g., topical application of compositions), at least oncedaily, for at least one week, or at least two weeks, or at least fourweeks, or at least eight weeks or more. In some embodiments, thecompositions are applied directly to a specific site of the skin (i.e.,directly onto a wrinkle and/or fine line, under the eyes, on a blemish,etc.). In some embodiments, the first and/or second and/or thirdcompositions will be applied to the skin in an amount from about 0.001to about 100 mg/cm², more typically from about 0.01 to about 20 mg/cm²,or from about 0.1 to about 10 mg/cm².

While the compositions and methods of the invention are contemplated tobe useful for treating (i.e., reducing, ameliorating, improving,alleviating, forestalling, slowing, remediating and/or eliminating) thedermatological effects of aging (chronological, hormonal, orphoto-aging) and/or environmental stress, they are also suitable for usein treating other dermatological conditions of the skin, includingwithout limitation excessive or unwanted pigmentation. Numerous areas ofthe body can be treated, including, without limitation, the face,forehead, lips, scalp, neck, arms, hands, legs, knees, feet, chest,back, groin, buttocks, thighs, and the like. In some embodiments, thecompositions are applied to the face, lips, chest, arms and/or hands,particularly, the face.

The cosmetically acceptable vehicle or carrier may be in the form of anemulsion. Non-limiting examples of suitable emulsions includewater-in-oil emulsions, oil-in-water emulsions, silicone-in-wateremulsions, water-in-silicone emulsions, wax-in-water emulsions,water-oil-water triple emulsions or the like having the appearance of acream, gel or microemulsions. As used herein, the term “oil” includessilicone oils unless otherwise indicated. The emulsion may include anemulsifier, such as a nonionic, anionic or amphoteric surfactant, or agellant, typically in an amount from about 0.001% to about 5% by weight.

The cosmetically acceptable vehicle may include water; vegetable oils;mineral oils; ester oils such as octal palmitate, isopropyl myristateand isopropyl palmitate; ethers such as dicapryl ether and dimethylisosorbide; alcohols such as ethanol and isopropanol; fatty alcoholssuch as cetyl alcohol, cetearyl alcohol, stearyl alcohol and behenylalcohol; isoparaffins such as isooctane, isododecane (IDD) andisohexadecane; silicone oils such as cyclomethicone, dimethicone,dimethicone cross-polymer, polysiloxanes and their derivatives,preferably organomodified derivatives including PDMS, dimethiconecopolyol, dimethiconols, and amodimethiconols; hydrocarbon oils such asmineral oil, petrolatum, isoeicosane and polyolefins, e.g.,(hydrogenated) polyisobutene; polyols such as propylene glycol,glycerin, butylene glycol, pentylene glycol, hexylene glycol, caprylylglycol; waxes such as beeswax, carnauba, ozokerite, microcrystallinewax, polyethylene wax, and botanical waxes; or any combinations ormixtures of the foregoing. Aqueous vehicles, including serums, mayinclude one or more solvents miscible with water, including loweralcohols, such as ethanol, isopropanol, and the like. The vehicle maycomprise from about 25% to about 99.9% by weight of the composition.

In one embodiment of the invention, any of the compositions may includeadditional skin actives, including but not limited to, retinoids,botanicals, keratolytic agents, desquamating agents, keratinocyteproliferation enhancers, collagenase inhibitors, elastase inhibitors,5-alpha reductase inhibitors, depigmenting agents, anti-inflammatoryagents, steroids, anti-acne agents, antioxidants, and advanced glycationend-product (AGE) inhibitors, to name but a few. The amounts of thesevarious ingredients are those conventionally used in the cosmetic fieldto achieve their intended purpose, and range individually orcollectively typically from about 0.001 wt % to about 20 wt % by weightof the composition. The nature of these ingredients and their amountsmust be compatible with the function of the compositions of thedisclosure.

Exemplary anti-aging components include, without limitation, botanicals(e.g., Butea frondosa extract, Tiliacora triandra extract, Portulacaoleracea, Melicope elyarana, etc.); hydroxy acids (includingalpha-hydroxy acids and beta-hydroxy acids), salicylic acid and alkylsalicylates; exfoliating agents (e.g., glycolic acid,3,6,9-trioxaundecanedioic acid, etc.), estrogen synthetase stimulatingcompounds (e.g., caffeine and derivatives); compounds capable ofinhibiting 5 alpha-reductase activity (e.g., linolenic acid, linoleicacid, finasteride, and mixtures thereof); and barrier function enhancingagents (e.g., ceramides, glycerides, cholesterol and its esters,alpha-hydroxy and omega-hydroxy fatty acids and esters thereof, etc.),to name a few.

Exemplary retinoids include, without limitation, retinoic acid (e.g.,all-trans, or 9-cis, or 13-cis), and derivatives thereof, retinaldehyde,retinol (Vitamin A) and esters thereof, such as retinyl palmitate,retinyl acetate and retinyl propionate, and salts thereof. Particularmention may be made of retinol. When present, the retinoids willtypically be included in amounts from about 0.0001% to about 5% byweight, more typically from about 0.01% to about 2.5% by weight, or fromabout 0.1% to about 1.0% by weight. Compositions according to thisembodiment will typically include an antioxidant such as ascorbic acidand/or BHT and/or a chelating agent such as EDTA or a salt thereof(e.g., disodium EDTA).

In another embodiment, the topical compositions of the present inventionmay also include one or more of the following: a skin penetrationenhancer; an emollient, such as isopropyl myristate, petrolatum,volatile or non-volatile silicones oils (e.g., methicone, dimethicone),ester oils, mineral oils, and fatty acid esters; a humectant, such asglycerin, hexylene glycol or caprylyl glycol; a skin plumper, such aspalmitoyl oligopeptide, collagen, collagen and/or glycosaminoglycan(GAG) enhancing agents; a sunscreen, such as avobenzone or octylmethoxycinnamate; an exfoliating agent; and an antioxidant.

Suitable tyrosinase inhibitors include thiodipropionic acid;hydroquinone; kojic acid; and others listed elsewhere in the instantapplication. Some skin tighteners or depigmenting agents, act asinhibitors of tyrosinase, an enzyme that has its catalytically activedomain within organelles known as melanosomes. Tyrosinase convertsphenols, including tyrosine, to ortho-quinones which are subsequentlyconvened to melanin within the melanosomes.

Suitable melanin inhibitors include niacinamide serine-proteaseinhibitors; and others listed elsewhere in the instant application.These may act by disrupting the transfer of the melanosomes frommelanocytes to the keratinocytes.

Suitable glycosaminoglycan (GAG) enhancing agents include, for example,phytol; terpene alcohols; peptides; PPAR modulators; and/or botanicals;and/or others listed elsewhere in the instant application.Glycosaminoglycans (GAGs) are produced by the body to maintainstructural integrity in tissues and to maintain fluid balance. GAGsserve as a natural moisturizer and lubricant between epidermal cells toinhibit the production of matrix metalloproteinases (MMPs)—enzymesactivated by UV exposure or inflammation that contribute to thebreakdown of collagen while inhibiting new collagen formation. TopicalGAG stimulants, GAG supplements and/or MMP inhibitors can help toprovide temporary restoration of enzyme balance to slow or preventmatrix breakdown and consequent onset of wrinkle formation.

Suitable collagen enhancing agents include retinoids; peptides;botanicals; and others listed elsewhere in the instant application.Collagen and elastin are the major components of the dermal-epidermaljunction (DEJ), i.e., a specialized structure mediating close contactbetween the lamina densa (the basement membrane zone between theepidermis and the dermis of the skin) and the underlying connectivetissue of the dermis. The dermal-epidermal junction (DEJ) includesinterlocking fingerlike projections called Rete ridges. The cells of theepidermis receive their nutrients and oxygen from the blood vessels inthe dermis because the epidermis does not have its own blood vessels.The Rete ridges at the DEJ increase the surface area of the epidermisthat is exposed to the dermis, so that the uptake of necessarynutrients/oxygen is more efficient, and the two layers of skin can bindmore strongly and resist mechanical stress. The DEJ flattens out withaging, such that the skin is more fragile and more likely to shear. Thisprocess also decreases the amount of nutrients/oxygen available to theepidermis by decreasing the surface area of the epidermis in contactwith the dermis, thereby interfering with the skin's normal repairprocess. As a result, the skin shows signs of aging such as fragility,lines and wrinkles, sagging, dull, discoloration, and uneven tone, roughtexture, and the like. The main structural component of the dermis isalso collagen. Bundles of collagen molecules pack together throughoutthe dermis, accounting for three-fourths of the dry weight of skin.Procollagen is the precursor molecule of collagen, synthesized in thefibroblast, osteoblast, etc., and cleaved to form collagenextracellularly. Collagen has great tensile strength, and along withsoft keratin, is responsible for skin strength and elasticity. As agingoccurs, the production of collagen is reduced, while the degradation isaccelerated due to an overproduction of collagenase, i.e., protease thatbreaks down collagen. Collagen deficiency may lead to reduction in skinstrength and elasticity, which in turn may lead to wrinkles, sagging,and fragility of the aging skin. For a more detailed background oncollagen, see Lodish, et al., Molecular Cell Biology, W.H. FREEMAN, NewYork, N.Y. 4.sup.th edition, 2000. Thus, it is anticipated that theretention of or stimulation of collagen and/or procollagen productionand/or the reduction in production of collagenase would provide for ahealthier and stronger skin, thereby reducing wrinkles, sagging, andfragility of the aging skin.

Suitable barrier enhancing agents include phytol, and ceramides, such asceramide-2, glycerides, cholesterol and its esters, alpha- andomega-hydroxy fatty acids and esters thereof, etc.); and others listedelsewhere in the instant application.

Suitable anti-inflammatory agents include thiodipropionic acid; andothers listed elsewhere in the instant application.

Suitable anti-cellulite agents (in one embodiment, intracellulartriglyceride inhibitors) include Coleus forskohlii; CPT-1 modulators;starfruit extract; caffeine; and others listed elsewhere in the instantapplication. Cellulite is the lumpy uneven type of subcutaneous fat thattends to accumulate on the buttocks, thighs, and limbs of many women. Itis considered unsightly because it gives the tissues underlying the skinan “orange peel” or “cottage cheese” look. Compressing the skin, as whensitting or crossing the legs, produces a “mattress appearance” withbulging and pitting of the fatty layer. Nodules of fat may be felttrapped within hardened connective tissue. The histology ofcellulite-affected skin indicates that cellulite results from acombination of enlarged fat tissue and weak dermal structure andconnective tissue septa. Excess fat accumulation increases the volume ofadipocytes, which bulge into a weakened dermis to create thecharacteristic irregularities in the appearance of the epidermalsurface. A number of factors can cause cellulite including, e.g.,hereditary, intestinal, circulatory, lymphatic, hormonal, and lifestylefactors. Dieting to decrease fat intake, exercising to increase fatmetabolism and prevent the build up of cellulite, and massage andhydrotherapy to stimulate lymphatic drainage can help reduce theappearance of cellulite. Nonetheless, these means for combatingcellulite or subcutaneous fat are limited, and the need remains foradditional approaches. The protrusion of enlarged fat tissue into thedermis is one of the major factors contributing to the appearance ofcellulite. One of the approaches to improve cellulite is to stimulatefat breakdown and reduce the amount of fat and/or lipids in theadipocytes, or fat cells.

Suitable hydroxyl acids and derivatives thereof include sodiumglycolate; oxa diacids; alpha-hydroxy acid; and others listed elsewherein the instant application.

Suitable retinoids and derivatives thereof include retinol; and otherslisted elsewhere in the instant application.

Suitable antioxidants include thiodipropionic acid; and others listedelsewhere in the instant application.

Suitable vitamins include niacinamide; and others listed elsewhere inthe instant application.

Suitable terpene alcohols include phytol; and others listed elsewhere inthe instant application.

Suitable peptides include K-ava-K; KTFK; n-acetyl tyrosinamide; andothers listed elsewhere in the instant application.

Suitable PPAR modulators include phytol and others listed elsewhere inthe instant application.

Suitable botanicals include Portulaca oleracea; Tiliacora triandara;Berchemia lineata; and others listed elsewhere in the instantapplication.

Suitable exfoliating agents include, for example, alpha-hydroxy acids,beta-hydroxy acids, oxa-acids, oxadiacids, and their derivatives such asesters, anhydrides and salts thereof. Suitable hydroxy acids include,for example, glycolic acid, lactic acid, malic acid, tartaric acid,citric acid, 2-hydroxyalkanoic acid, mandelic acid, salicylic acid andderivatives thereof. One exemplary exfoliating agent is glycolic acid.When present, the exfoliating agent may comprise from about 0.001% toabout 20% by weight of the composition.

Examples of antioxidants that may be used in the present compositionsinclude compounds having phenolic hydroxy functions, such as ascorbicacid and its derivatives/esters; beta-carotene; catechins; curcumin;ferulic acid derivatives (e.g., ethyl ferulate, sodium ferulate); gallicacid derivatives (e.g., propyl gallate); lycopene; reductic acid;rosmarinic acid; tannic acid; tetrahydrocurcumin; tocopherol and itsderivatives, including tocopheryl acetate; uric acid; or any mixturesthereof. Other suitable antioxidants are those that have one or morethiol functions (—SH), in either reduced or non-reduced form, such asglutathione, lipoic acid, thioglycolic acid, and other sulfhydrylcompounds. The antioxidant may be inorganic, such as bisulfites,metabisulfites, sulfites, or other inorganic salts and acids containingsulfur. Antioxidants may comprise, individually or collectively, fromabout 0.001% to about 10% (w/w), or from about 0.01% to about 5% (w/w)of the total weight of the composition.

Other additives include: vitamins, such as tocopherol and ascorbic acid;vitamin derivatives such as ascorbyl monopalmitate, tocopheryl acetate,and Vitamin E palmitate; thickeners such as hydroxyalkyl cellulose,carboxymethylcellulose, carbombers, and vegetable gums such as xanthangum; gelling agents, such as ester-terminated polyester amides;structuring agents; metal chelating agents such as EDTA or saltsthereof; pigments; colorants; and pH adjusters (citric acid,ethanolamine, sodium hydroxide, etc.). The composition may optionallycomprise other components known to those skilled in the art including,but not limited to, film formers, moisturizers, minerals, viscosityand/or rheology modifiers, anti-acne agents, insect repellents, skincooling compounds, skin protectants, lubricants, fragrances,preservatives, stabilizers, and mixtures thereof. In addition to theforegoing, the cosmetic compositions of the invention may contain anyother compound for the treatment of skin disorders.

In addition, the compositions contemplated by this disclosure caninclude one or more compatible cosmetically acceptable adjuvantscommonly used and known by the skilled practitioner, such as colorants,pearls, chromalites, micas, pigments, dyes, fragrances, emollients,humectants, preservatives, vitamins, chelators, thickeners, anesthetics,anti-allergenics, antifungals, antimicrobials, other anti-inflammatoryagents, antioxidants, antiseptics, depigmenting agents, film formers,insect repellents, pharmaceutical agents, photostabilizing agents,sunscreens, stabilizers, surfactants, thickeners, viscosity modifiers,and botanicals. The topical compositions of the present disclosure mayalso include a skin penetration enhancer, a surface smoother, a skinplumper, an optical diffuser, an exfoliation promoter, and anantioxidant. Details with respect to these and other suitable cosmeticingredients can be found in the “International Cosmetic IngredientDictionary and Handbook,” 10th Edition (2004), published by theCosmetic, Toiletry, and Fragrance Association (CTFA), at pp. 2177-2299,which is herein incorporated by reference in its entirety. The amountsof these various substances are those that are conventionally used inthe cosmetic or pharmaceutical fields, for example, they can constitutefrom about 0.01% to about 20% of the total weight of the composition.

A sunscreen may be included to protect the skin from damagingultraviolet rays. In an illustrative embodiment of the presentdisclosure, the sunscreen provides both UVA and UVB protection, by usingeither a single sunscreen or a combination of sunscreens. Among thesunscreens that can be employed in the present compositions areavobenzone, cinnamic acid derivatives (such as octylmethoxy cinnamate),octyl salicylate, oxybenzone, octocrylene, titanium dioxide, zinc oxide,or any mixtures thereof. The sunscreen may be present from about 1 wt %to about 30 wt % of the total weight of the composition.

In one embodiment, the topical compositions will have a pH range from 1to 13, with a pH in the range of from 2 to 12 being typical. In someembodiment, the composition will have a pH in the range of from 3.5 to 7or from 7-10.5. In some embodiments, the pH will be in the range of 3-4,or 4-5, or 5-6, or 6-7, or 7-8, or 8-9, or 9-10, or 10-11, or 11-12.Suitable pH adjusters such as sodium hydroxide, citric acid andtriethanolamine may be added to bring the pH within the desired range.

It will be understood that the foregoing optional active and inactiveingredient(s) may be included in one or all of the compositionsaccording to the inventions (e.g., both the first and the secondcompositions).

Another embodiment of the present disclosure is directed to the deliveryof the described compositions by the use of targeted delivery systems,for example, liposomes, injection, microspheres, (see, e.g., U.S. Pat.No. 5,770,222 to Unger et al.), and the like, so that the componentsand/or active constituents can more readily reach and affect thesubcutaneous layer of the area of application, e.g., face or neck, orthe other area of the skin.

The compositions may be formulated in a variety of product forms, suchas, for example, a lotion, cream, serum, spray, aerosol, cake, ointment,essence, gel, paste, patch, pencil, towelette, mask, stick, foam,elixir, concentrate, and the like, particularly for topicaladministration. The compositions are typically formulated as a lotion,cream, ointment, or gel. The first and second compositions may also takedifference forms from one another.

In certain embodiments of the invention, the compositions are appliedtopically to improve the appearance and/or health of human skin. Theimprovement in the appearance and/or health of human skin may be animprovement of any attribute or characteristic of skin, includingwithout limitation:

-   -   (a) treatment, reduction, and/or prevention of fine lines or        wrinkles;    -   (b) reduction of skin pore size;    -   (c) improvement in skin thickness, plumpness, and/or tautness;    -   (d) improvement in skin smoothness, suppleness and/or softness;    -   (e) improvement in skin tone, radiance, and/or clarity;    -   (f) improvement in procollagen, and/or collagen production;    -   (g) improvement in maintenance and remodeling of elastin;    -   (h) improvement in skin texture and/or promotion of        retexturization;    -   (i) improvement in skin barrier repair and/or function;    -   (j) improvement in appearance of skin contours;    -   (k) restoration of skin luster and/or brightness;    -   (l) replenishment of essential nutrients and/or constituents in        the skin;    -   (m) improvement of skin appearance decreased by aging and/or        menopause;    -   (n) improvement in skin moisturization;    -   (o) increase in skin elasticity and/or resiliency;    -   (p) treatment, reduction, and/or prevention of skin sagging;    -   (q) improvement in skin firmness; and    -   (r) reduction of pigment spots and/or mottled skin; and    -   (s) improvement of optical properties of skin by light        diffraction or reflection.

In some embodiments, the compositions are intended to treat winklesand/or fine lines in the skin, including forehead wrinkles, “crow'sfeet,” and wrinkles at the edges of the eyes or mouth. In someembodiments, the compositions are applied directly to a wrinkle and/orfine line. The treatment may reduce the severity (e.g., depth) of thewrinkles and fine lines and/or may reduce the number of wrinkles and/orfine lines in a given area of skin. In some embodiments, thecompositions are intended to treat sagging skin which may result from aloss of dermal elasticity. In this embodiment, the compositions may beapplied to skin of the checks, jowls, etc.

It is also contemplated that the methods of the invention will be usefulfor treating thin skin by topically applying the composition to thinskin of an individual in need thereof. “Thin skin” is intended toinclude skin that is thinned due to chronological aging, menopause, orphoto-damage and skin that is thinning prematurely. In some embodiments,the treatment is for thin skin in men, whereas other embodiments treatthin skin in women, pre-menopausal or post-menopausal, as it is believedthat skin thins differently with age in men and women, and in particularin women at different stages of life.

The methods of the invention may be employed prophylactically toforestall aging including in individuals that have not manifested signsof skin aging, most commonly in individuals under 25 years of age. Themethods may also reverse or treat signs of aging once manifested as iscommon in individuals over 25 years of age, or to slow the progressionof dermatological aging in such individuals.

In certain embodiments, the cosmetic compositions described herein canbe used to treat and/or prevent hyper-pigmentation of skin and/or of thehair, for example, to lighten skin or hair. In some embodiments, thecompositions are topically applied to the skin or hair, for example toan area of hyper-pigmented skin or hair. Hyper-pigmentation includes anycoloration of an individual's skin or hair that is darker than desiredby the individual and that is caused by melanocytes. Such unwantedpigmentation may also be called discoloration. Hyper-pigmented areas ofthe skin include areas of discrete or mottled hyper-pigmentation. Areasof discrete hyper-pigmentation can be distinct, uniform areas of darkercolor and may appear as brown spots or freckles on the skin, includingmarks commonly called pigment spots or “age spots.” Areas of mottledhyper-pigmentation of the skin can be dark blotches that are larger andmore irregular in size and shape than areas of discrete pigmentation.Areas of hyper-pigmentation also include areas of tanned skin, forexample, skin tanned due to UV exposure. Hyper-pigmented hair includesany shade of hair that is darker than desired.

Treating hyper-pigmentation or hyper-pigmented skin/hair refers toeradicating, reducing, ameliorating, or reversing one or more of theunwanted features associated with hyper-pigmentation, such as producinga perceptible lightening of the skin or hair in the affected area.Lightening hyper-pigmented areas of the skin may be desirable, in oneembodiment, in diminishing age spots; lightening a suntan; evening oroptimizing skin tones, e.g., in areas of mottled hyper-pigmentation; intreating melasmic and chloasmic patches, freckles, after-burn scars, andpost-injury hyper-pigmentation. Preventing hyper-pigmentation orhyper-pigmented skin refers to affording skin, not yet affected byhyper-pigmentation, a benefit that serves to avoid, delay, forestall, orminimize one or more unwanted features associated with skinhyper-pigmentation, such as reducing the darkness or size ofhyper-pigmented areas that eventually develop.

In one embodiment, the compositions of the invention are applied tohuman skin to reduce sebum production or improve the appearance of skinaffected by cellulite, and/or reduce unwanted lipogenesis or increaselipolysis. In this embodiment, the terpene alcohols and/or retinoids canbe formulated in cosmetically acceptable vehicles (as described herein)and may include one or more additional agents such as anti-acneingredients (e.g., salicylic acid, benzoyl peroxide and other peroxides,sulfur, retinoids, etc.) in the case of a facial composition, or, in thecase of a cellulite treatment, the formulation may comprise anyingredients suitable for treatment of cellulite, including withoutlimitation, Coleus forskohlii, perilla oil and other unsaturated fattyoils and omega-3 fatty acids such as alpha-linolenic acid; conjugatedlinoleic acid (CLA); caffeine; theophylline; xanthines; retinoids (e.g.,retinol); epigallocatechin gallate; and the like. A cellulite treatmentcomposition according to the invention may comprise effective amounts ofa lipolysis stimulator, lipogenesis inhibitor, or an adipogenesisinhibitor. The cellulite treatment may comprise a PPAR ligand, which maybe an inhibitor of upregulation of any of the PPAR isoforms, such asPPAR-α and/or PPAR-γ. The cellulite treatment may comprise CPT-1inhibitor, for example and extract of Star Fruit. A cellulite treatmentaccording to the invention will typically be applied topically to skinsuffering from cellulite, including skin of the buttocks and thighs fora period of time sufficient to improve the appearance thereof, includingfor example, daily treatment for at least four weeks, at least eightweeks, at least twelve weeks, or longer. In one embodiment, thecompositions are topically applied to treat acne.

In one embodiment, the compositions are intended for use as anon-therapeutic treatment. In another embodiment, the compositions arearticles intended to be rubbed, poured, sprinkled, or sprayed on,introduced into, or otherwise applied to the human body for cleansing,beautifying, promoting attractiveness, or altering the appearance, inaccordance with the US FD&C Act, §201(i).

In another embodiment, a kit and/or a method of periodic or rotationalskincare treatment is contemplated. The kit may comprise: (i) a of aplurality of topical compositions comprising a physiologicallyacceptable vehicle; (ii) a second of a plurality of topical compositionscomprising a physiologically acceptable vehicle, said first topicalcomposition being physically separated from said second topicalcomposition, and (iii) optionally, written instructions for topicallyapplying said first and second topical compositions in alternatingfashion, in any order, such that the first composition is applied atleast once daily for a first period of time from 1-31 days and saidsecond composition is applied at least once daily for a second period oftime from 1-31 days.

In one embodiment, the plurality of compositions are each contained in aseparate container as a single ingredient, wherein multiplesingle-formula containers (for example, jars and dispensers) are soldand/or packaged together.

In another embodiment, the plurality of compositions exist as differentphysical layers within the same container (for example, separated bydensity and/or miscibility of layers), which may be packaged in jars,dispensers, and/or other container types.

In another embodiment, the plurality of compositions are contained indifferent sachets that may themselves be packages and/or sold together,and that may be arrayed linearly; in a matrix; and/or radially.

In another embodiment, the plurality of compositions are contained indifferent bliser packs that may themselves be packaged and soldtogether, and that may be arrayed linearly; in a matrix; and/orradially.

In another embodiment, the plurality of compositions are contained indifferent reservoirs within the same package.

In another embodiment, the plurality of reservoirs each comprise asingle dose of said first and second topical compositions, respectively.

In another embodiment, the plurality of reservoirs are not separablefrom one another.

In another embodiment, the plurality of reservoirs are marked with aplurality of different identifiers (e.g., color, symbol, light, display,QR code, etc.), respectively.

In another embodiment, an identifier (e.g. color, symbol, light,display, QR code, etc.) is utilized to indicate to the user to switchuse from a first composition to a second composition and/or whichcomposition to use on a given treatment opportunity. In anotherembodiment, the packaging contains an indicator light that indicateswhether the user should apply the first composition or the secondcomposition. In another embodiment, the first and/or second containerscontain an electronic display that indicates whether the user shouldapply the first composition or the second composition.

In another embodiment, written instructions indicate to the user whichtreatment modality to use on a particular day by reference to theplurality of identifiers.

In another embodiment, the order of treatment modalities to use isstochaistic or randomly generated.

In another embodiment, the method or kit further includes a calendar,the calendar identifying a first time period comprising from 1-31 days,said first time period being marked with said first identifier, and asecond time period comprising from 1-31 day, said second time periodbeing marked with said second identifier. In another embodiment, themethod or kit further includes written instructions (e.g., a QR code)for accessing a calendar over the Internet, wherein said calendarinstructs the user whether to apply the first or second compositiondepending on the day. In one embodiment, the calendar will have, on eachday, an indicator or symbol uniquely identifying one of thecompositions, which may, for example, be packed in containers orreservoirs also identified by the same indicators or symbols.

In another embodiment, the method or kit further includes writteninstructions for accessing data over the Internet (e.g., a QR code),wherein the data (in, for example, the form of an algorithm orapplication or in the form of a text message or other datacommunication) provides the user with instruction as to which treatmentmodality to apply; and where the data may be accessible through asmartphone application, Website, etc.

In other embodiments, a system is provided comprising a skin careproduct and a server and optionally a computer remote from the server.The skin care product may be as described herein, and may, for example,have separated in different reservoirs within the same packaging orcontainer, two different skin treatment compositions that may beindependently dispensed from said packaging or container; and anindicator for distinguishing between said skin treatment compositions.The server is typically configured to receive, over a computer network,from a user of said skin care product, a date on which a skin treatmentregimen is started, and configured to send, over a computer network, tosaid user a plurality of notifications on a plurality of different daysinstructing the user as to which of said first or second skin treatmentcompositions to topically apply to said skin. The skin care product mayfurther comprise an identifier (e.g., alpha-numberic code, barcode, QRcode, etc.) which is capable of identifying said skin treatmentcompositions, and the server may be configured to receive saididentifier from the user in addition to a start date. Based on theidentifier, the server may use information regarding first and secondcompositions in the particular product and the said start date tocalculate the treatment regimen for the said first and secondcompositions. For example, the server may be instructed to use aparticular value for the first period of time and particular value forthe second period of time based on the identifier. The server may beconfigured to send, over a computer network, to said user a plurality ofnotifications on a plurality of different days instructing the user asto which of said first or second skin treatment compositions totopically apply to said skin, based on the user input of a start dateand a predetermined duration of the first and second periods of time.The system may further comprise a computer remote from the server (e.g.,cell phone, telephone, smart phone, tablet, wearable device, watch,pager, computer, laptop, etc.), under the control of the user, forsending the start date to said server and for receiving the plurality ofnotifications.

Referring now to FIG. 6, a flow chart illustrates the process and systemin which a user, for example, via a computer (e.g., smartphone, laptop,desktop computer, etc.), sends a start date and said server receivessaid start date at step 100. The sending and receiving may occur over anetwork, such as the Internet, a wireless network, land lines,satellite, etc. Based on the start date, the server determines aschedule for the first treatment modality using the predetermined firstperiod of time (typically from 1-31 days, or 2-15 days, or 7 days), atstep 200. This may entail adding the first period of time to the startdate. The user would apply a first composition from the product duringthis first period of time. The server may notify (e.g., by text message,email, social media post, telephone, etc.) the user one or more times(e.g., daily) during the first treatment time to apply the firstcomposition on that day. Alternatively, the server may notify the useronly when it is time to change the treatment to the second composition,e.g., prior to the end of, or at the end of, the first treatment periodat step 300. The server may use the start date to determine an end datefor the first treatment regimen, based on predetermined or user suppliedinput of a first treatment period of time. For example, the firsttreatment period may be seven days, which may be a predeterminedinstruction on said server or may be inputted or selected by the user.Prior to the end date of the first treatment modality, the server maycalculate the start and end dates of a second treatment modality, againbased on pre-determined input or based on user supplied input for thedesired duration of the second treatment regimen at step 400. This mayentail adding the first period of time and second period of time to thestart date, or adding the second period of time to the value determinedin step 200 (i.e., the end of the first treatment schedule). The servermay notify the user prior to the end of, or at the end of, the secondtreatment regimen to begin the first treatment regimen on a certain dateat step 500. The server may repeat steps 200-500 for any number ofiterations, typically more than four. The number of iterations based onpre-determined input or based on user supplied input. On the second orany greater iteration, the server may repeat steps 200-500 based on thestart date, the length of the first and second periods of time, and theiteration number. Alternatively, the server may send notifications ofany first or second treatment modality during any previous first orsecond periods of time.

In another embodiment, the user may scan or image their treatedintegument, for example, using the camera of a smartphone, and send thescan or image to the server. The server may be configured to generatecustomized instructions on further treatment from Internet data orapplication, and send those instructions to the user's computer over thenetwork.

In another embodiment, first and second compositions are contained inseparate reservoirs within a single container, wherein the container hasa first pump in fluid communication with the reservoir containing thefirst composition for dispensing said first composition and a secondpump in fluid communication with the reservoir containing the secondcomposition for dispensing said second composition, each pump optionallybeing disposed on opposite side of said container, and each pumpoptionally being covered by a removable cap such that the user removesthe cap from one end while holding the cap that covers the other end.

Referring now to FIGS. 7 and 8, a skincare product 10 is illustratedcomprising a container 12 comprising a first reservoir 14 containing afirst skin treatment composition 60 and a second reservoir 16 containinga second skin treatment composition 62, different from said first skintreatment composition, a first pump 26 in fluid communication with thefirst reservoir 14 for dispensing said first skin treatment composition,and a second pump 22 in fluid communication with the second reservoir 16for dispensing said second skin treatment composition. The first andsecond pumps may be the same or different. Any suitable pump used inpersonal care or cosmetic arts is contemplated to be suitable. FIG. 7shows a view illustrating the internal contents of reservoirs 14 and 16distinguished as a first composition 60 and a second composition 62.Referring to FIGS. 9-11, cross sectional views of the product 10 areshown. As illustrated, the pumping mechanisms 20 and 22, in thisembodiment, comprise tubes 21 and 23 for conveying liquid compositionsfrom each reservoir and dispensing them through orifices 26 and 28.Springs 25 and 27 actuate the pump according to well-known designs. Abarrier 40 separates the first reservoir from the second reservoir.Barrier 40 may be integral with the container 12 such that the tworeservoirs cannot be separated from one another. Removable caps 30 and32 are attached at each respective end of the container and cover thepumps 20 and 22 when seated on the container. Referring to FIGS. 12A and12B, an embodiment of the skincare product is shown, wherein theexterior of the container or its labeling affixed thereto bearsalpha-numeric indicators “1” and “2” distinguishing the first and secondreservoirs. The product according to this embodiment, may includevisible identifiers 50 indicating each day of the week, for example,printed on a label affixed to the container. In FIG. 12B, the producthas a circular sticker 55 placed by the user onto the appropriate day ofthe week on which the treatment regimen began (for example, Monday or“M”), to serve as a reminder to alternate between the first and secondtreatment compositions every week on that particular day.

In another embodiment, a plurality of compositions may be contained in aplurality of separate reservoirs within a single container, wherein thecontainer contains a pump in fluid communication with the reservoircontaining the first composition for dispensing said first compositionand a pump in fluid communication with the reservoir containing thesecond composition for dispensing said second composition, wherein thepumps form a multi-sided toggle mechanism (e.g., toggle pump), such thatactuation of the toggle mechanism to deliver a first composition willprime the actuating mechanism to deliver a second composition optionallywhile preventing actuation of the toggle mechanism to deliver the firstor any other composition until the primed toggle is actuated to deliverthe second composition.

In another embodiment, a plurality of single-use, optionally refillablecapsules may be utilized, each capsule comprising a reservoir containinga unit dose of a topical composition and a dispenser for dispensing saidcomposition, wherein at least one of said capsules contains a firsttopical composition and at least one of said capsules contains a secondtopical composition; wherein the plurality of capsules are removablyattached directly or indirectly to one another, and may be individuallyseparated from the plurality prior to dispensing the topical compositioncontain therein.

In another embodiment, the capsules containing said first topicalcomposition are visually distinct from the capsules containing saidsecond topical composition.

In another embodiment, the dispenser comprises a breakable plugconfigured to expose an orifice in said capsule when broken.

In another embodiment, the first and second compositions are containedin separate reservoirs within a single container, wherein at least oneof the compositions is in the form of a clear gel, and at least aportion of the wall of said container is transparent or translucent suchthat the first and/or second composition is visible through said portionof said container wall, and wherein the container has an indicator forilluminating said clear gel composition to indicate when thatcomposition should be applied.

In another embodiment, a plurality of compositions are contained inseparate reservoirs within a single container, and wherein a rotatingdispenser is configured to dispense either the first composition or thesecond composition through a common opening depending on the degree ofrotation of the rotating dispenser.

In another embodiment, a kit or method is utilized comprising: (i) oneor more compositions comprising a physiologically acceptable vehicle andan effective amount of a skincare active; (ii) at least one device forimparting mechanical or electromagnetic energy to the skin, and (iii)written instructions for topically applying said first topicalcompositions for a first period of time and using said device on thesame area of skin for a second period of time, in any order, andrepeating one or more times. The device may impart light; irradiate;deliver a radio frequency; deliver heat; deliver an electrical current;deliver cold; buff; exfoliate; impart suction; oxygenate; or otherwiseapply a phenomenon to the skin.

EXAMPLES

The following example illustrates a specific aspect of the instantdescription. The example should not be construed as limiting, as theexample merely provides specific understanding and practice of theembodiments and its various aspects. In each of the following examplesthat use an extract of the Tiliacora triandra plant, the extract wasprepared from hydroponically grown Tiliacora triandra and extracted witha 80/20 (v/v) ethanol/water solvent.

Example 1

Human dermal fibroblast cells were grown in a 6-well plate in DMEM media(available from Corning, NY) supplemented with 10% Fetal Bovine Serum(FBS) and L-glutamine (1.5×10⁵ cells/plate) overnight. After reachingabout 75% confluence, cells were transferred into DMEM media without FBSand incubated for 4-6 hours. Next, the cells were treated with either0.0001% phytol or 1 μM retinol. Treatment with either phytol alone, orretinol alone was performed in DMEM media without FBS for 16 days. Forsequential treatments, the cells were treated with 0.0001% phytol for 6days followed by 1 μM retinol for 10 days, or with 1 μM retinol for 6days, followed by 0.0001% phytol for 10 days. Every other day, mediawere collected and cells were re-treated with phytol or retinol in thesame fashion. After treatment, the amount of collagen secreted into theculture media was determined using the HTRF human pro-collagen I kit(available from CISBIO, Inc).

The results are shown in FIGS. 1-2. FIG. 1 depicts levels ofpro-collagen in the cells treated with either phytol or retinol alone.The pro-collagen production declines for both phytol- andretinol-treated cells after day 13 despite continuing treatment. FIG. 2shows collagen production for untreated (“control”) cells,phytol-treated cells, retinol-treated cells, as well as cells firsttreated with retinol followed by phytol, and cells first treated withphytol followed by retinol. It is apparent that cells treated insequential fashion show increased collagen production as compared tocells treated with a single active.

Example 2

The clinical efficacy of a rotational regimen was demonstrated asfollows.

Subjects (age range: 24-59) having mild-to-moderate fine lines andwrinkles were recruited for the study. The subjects were allocated totwo groups: Cell 1 received a treatment regimen comprising topicalapplication of an α-hydroxy acid (AHA) formulation once daily for oneweek followed by topical application of a retinol formulation once dailyto the same area of skin on the face for one week. These treatments werecontinued in rotating fashion for a total of 12 weeks. The subjects inCell 2 received only the topical retinol treatment once daily for theentire 12 weeks. All subjects underwent a two week pre-conditioningduring which they received no AHA or retinol therapy. All subjectsapplied a sunscreen to the face daily during the conditioning period andthroughout the 12 week trial.

The α-hydroxy acid (AHA), e.g., glycolic acid, and Retinol formulationsthat were used in this study are provided below in Table 1.

TABLE 1 AHA Retinol Formula Formula Ingredient (wt. %) (wt. %)Oil-in-water emulsion base q.s. q.s. Retinol — 0.1 Glycolic Acid (70%)4.63 — Phytol 1 — Sodium Ascorbate — 0.2 Thiodipropionic Acid 1 —Trioxaundecanedioic Acid (90%) 1.4 —

The area of application was evaluated and scored by a dermatologist atbaseline and after 4, 8, and 12 weeks.

The results are summarized below in Table 2.

TABLE 2 Mean % Magnitude of Improvement from Baseline 90th PercentileMagnitude of Improvement from Baseline [% of Panelists with Improvementfrom Baseline] Week 4 Week 8 Week 12 Cell 1 Cell 2 Cell 1 Cell 2 Cell 1Cell 2 Parameter (N = 32) (N = 32) (N = 31) (N = 31) (N = 31) (N = 31)Texture 36 35 39 40 44 43 50 50 50 50 60 50 [97] [100]  [97] [100]  [97][100]  Even Skin 23 20 29 25 33 30 Tone 33 33 40 40 50 50 [81] [74] [97][84] [97] [90] Lack of 34 29 38 35 42 37 Clarity 50 50 50 50 60 50[100]  [94] [100]  [100]  [100]  [97] Discrete 14  9 19 17 25 19Pigmentation 33 50 50 50 50 50 [42] [19] [52] [45] [58] [55] Mottled 18— 23 15 29 19 Pigmentation 50 50 50 67 50 [48] [52] [42] [61] [52] FineWrinkles 24 22 34 32  45* 40 (Overall) 25 25 50 50 50 50 [94] [84][100]  [100]  [100]  [100]  Coarse  6  7 20 19 22 20 Wrinkles 25 25 3333 40 33 (Overall) [23] [26] [77] [71] [77] [74] *Statisticallysignificant (p ≤ 0.05) improvement over retinol treatment (Cell 2).

As shown in Table 2, improvements from baseline were noted as early asfour weeks after the start of the study, with marked improvements inskin tone, clarity, and reduction in discrete pigmentation. By twelveweeks a statistically significant reduction in the appearance of finelines was found for the rotational treatment group (Cell 2) compared tothe retinol treatment group (Cell 1). This result was surprising becausethe rotational group (Cell 1) received half the total dose of retinolthat the retinol group received, and AHA therapy is not generallyregarding as being capable of achieving the magnitude of wrinkle/fineline reduction as retinol.

Examples 3-10

Hyaluronic Acid (HA) Assessment in Human Dermal Fibroblasts

A series of experiments was conducted to assess the effects of thetreatment regimens of active ingredients on the production of hyaluronicacid (HA) in human dermal fibroblast (HDF) cells. The following fivetreatment regimens were assessed: (1) active ingredient A, alone; (2)active ingredient B, alone; (3) the combination of active ingredientsA+B; (4) active ingredient A, alone, followed by active ingredient B,alone (“A/B”); and (5) active ingredient B, alone, followed by activeingredient A, alone (“B/A”). For treatment regimens (1), (2), and (3),the active ingredients were administered to cells for 10 consecutivedays. For treatment regimens (4) and (5) (sequential regimens), thecells were treated with active ingredient A or active ingredient B for 5days, followed by active ingredient B or active ingredient A for 5 days,respectively.

Human dermal fibroblast cells were grown in 96-well plates in DMEM media(available from CORNING, N.Y.) supplemented with 10% FBS andL-glutamine. After reaching about 75% confluence, cells were transferredinto DMEM media without FBS, and incubated for 4-6 hours. Differentwells were assigned to one of treatment regimens (1)-(5) as describedabove, with six wells allocated to each treatment regimen (i.e., n=6).All active ingredients were prepared as emulsions and applied directlyto the HDF cells. The specific active ingredients used in each of thefive treatment regimens are provided below in Table 3. Followingtreatment, cells were collected and the amount of hyaluronic acid (HA)secreted from the cells was measured using a commercially available HAassay (available from CORGENIX Inc., CO).

TABLE 3 Ex. Active A [A] Active B [B] 3 Tiliacora 0.10% Niacinamide0.10%  triandra 4 Retinol 1 μM Coleus 0.001%  forskohlii 5 Glycolic 1 mMNiacinamide 0.1% Acid 6 KTFK 0.001%  Tiliacora 0.1% triandra 7 Glycolic1 mM Tiliacora 0.1% Acid triandra 8 Glycolic 1 mM Tetrapeptide 4 0.10% Acid 9 Sodium 10 μM Phytol 0.010%  Glycolate 10 Sodium 10 μM Retinol 1μM Glycolate

The results are summarized below in Table 4 and plotted in FIGS. 13-17as a percentage change over control (i.e. cells treated with the sameemulsion but in absence of active ingredients).

TABLE 4 A alone B alone A + B A/B B/A (% change (% change (% change (%change (% change Ex. in HA) in HA) in HA) in HA) in HA) 3 49.5 −51.67.87 45.2 80.2 4 11.7 −3.04 19.9 — 34.9 5 20.8 −51.6 −6.9 30.6 11.6 623.7 49.5 186.7 120.7 87.6 7 20.8 49.5 100 98.8 63.2 8 20.8 15.1 38.1−5.52 0.0 9 −2.54 67.7 −6.47 15.6 — 10 −2.54 11.7 27.5 26.3 —

As shown in Table 4 and FIGS. 13-17, sequential treatment of certainactive ingredients is effective in stimulating HA production. Thesequential treatment resulted in a more than additive improvement inExamples 3-6 and 10. Examples 3-5 and 10 each showed statisticallysignificantly greater production of HA, compared with when those activeingredients are used alone or simultaneously. For example, Example 3(see FIG. 11) demonstrates that sequential treatment of niacinamidefollowed by Tiliacora triandra extract results in higher levels of HAproduced than with treatment by Tiliacora triandra alone, niacinamidealone, or simultaneous application of Tiliacora triandra andniacinamide.

Example 11

Measurement of HA in full thickness 3D skin models for rotationaltreatment regimens.

A series of experiments was conducted to assess the effects of thetreatment regimens of glycolic acid and Tiliacora triandra on theproduction of hyaluronic acid (HA) on full thickness 3D skin cultures.Five different treatment regimens were assessed: (1) 4% glycolic acid,alone; (2) 0.2% Tiliacora triandra, alone; (3) the combination of 4%glycolic acid+0.2% Tiliacora triandra; (4) 4% glycolic acid, alone,followed by 0.2% Tiliacora triandra, alone; and (5) 0.2% Tiliacoratriandra, alone, followed by 4% glycolic acid, alone. Glycolic acid wasadministered topically to the 3D tissue and Tiliacora triandra wasadministered via the growth media. For treatment regimens (1), (2), and(3), the active ingredient or ingredients were applied to cells for 4consecutive days. For treatment regimens (4) and (5) (sequentialregimens), the cells were treated with glycolic acid or Tiliacoratriandra for 2 days, followed by Tiliacora triandra or glycolic acid for2 days, respectively.

Human 3D skin EFT400FT tissues (MatTek, MA) were cultured following themanufacturer's instructions. Each treatment regimen was applied totwelve 3D skin samples. Different 3D skin samples were assigned to oneof treatment regimens (1)-(5) as described above, with twelve skintissue models allocated to each treatment regimen (i.e., n=12).Following treatment, cells were collected and the amount of hyaluronicacid secreted from the cells was measured using a commercially availableHA assay (available from CORGENIX Inc., CO).

TABLE 5 Glycolic Glycolic Tiliacora Acid + Acid/ triandra/ GlycolicTiliacora Tiliacora Tiliacora Glycolic Acid triandra triandra triandraAcid 42.6 36.1 79.2 88.4 −29.4

The results are shown in Table 5 and plotted in FIG. 18 as a percentagechange over control (i.e., models treated with the same emulsion but inabsence of active ingredients). Sequential treatment with glycolic acidfollowed by Tiliacora triandra extract is effective in stimulating HAproduction. Example 11 (see FIG. 16) demonstrates that a sequentialtreatment of glycolic acid followed by Tiliacora triandra results instatistically significant higher levels of HA produced than withtreatment by either active alone.

Examples 12-13

Pro-Collagen Type I Assessment in Human Dermal Fibroblasts

A series of experiments was conducted to assess the effects of thetreatment regimens of active ingredients shown in Table 6 on theproduction of pro-collagen type I in human dermal fibroblast (HDF)cells. Five different treatment regimens were assessed: (1) activeingredient A, alone; (2) active ingredient B, alone; (3) the combinationof active ingredients A+B; (4) active ingredient A, alone, followed byactive ingredient B, alone; and (5) active ingredient B, alone, followedby active ingredient A, alone. For treatment regimens (1), (2), and (3),the active ingredients were applied to cells for 10 consecutive days.For treatment regimens (4) and (5) (sequential regimens), the cells weretreated with either active ingredient A or B for 5 days, followed bytreatment with the other active ingredient B or A for 5 days,respectively.

Human dermal fibroblast cells were grown in 96-well plates in DMEM media(available from CORNING, NY) supplemented with 10% FBS and L-glutamine.After reaching about 75% confluence, cells were transferred into DMEMmedia without FBS, and incubated for 4-6 hours. Different wells wereassigned to one of treatment regimens (1)-(5) as described above, withsix wells allocated to each treatment regimen. All active ingredientswere prepared as emulsions and applied directly to the HDF cells. Thespecific active ingredients used in each of the five treatment regimensare provided below in Table 6. Following treatment, measurements on theamount of pro-collagen produced from the cells were performed using acommercially available pro-collagen type I enzyme-linked immuno sorbentassay (ELISA) kit (available from TAKARA Inc., KR).

TABLE 6 Ex. Active A [A] Active B [B] 12 Retinol 1 μM Coleus 0.001%forskohlii 13 Phytol 0.0001% Retinol 1 μM

The results are shown in Table 7 and plotted in FIGS. 19-20 as apercentage change from control (i.e., cells treated with same emulsionbut in absence of active ingredients).

TABLE 7 A alone B alone A + B A/B B/A (% change (% change (% change (%change (% change in pro- in pro- in pro- in pro- in pro- Ex. collagen)collagen) collagen) collagen) collagen) 12 13.6 12.3 4.7 — 26.8 13 19.13.9 — 75.7 92.6

As shown in Table 7, sequential treatment of Coleus forskohlii extractfollowed by retinol in human dermal fibroblast cells results instatistically significant improvement in pro-collagen type I productionas compared to treatment using retinol alone, Coleus forskohlii alone,or simultaneous application of retinol and Coleus forskohlii. Similarly,it is apparent that sequential treatments of phytol/retinol (AB) andretinol/phytol (B/A) on HDF cells produce statistically significantlymore pro-collage type I than treatments to cells with either active. Thesequential treatment of retinol/phytol resulted in a more than additiveimprovement in Example 13.

Examples 14-16

Melanin in 3D Skin Models

A series of experiments was conducted to assess the effects of treatmentregimens of active ingredients shown in Table 8 on the production ofmelanin in 3D models. Four different treatment regimens were assessed:(1) active ingredient A, alone; (2) active ingredient B, alone; (3) thecombination of active ingredients A+B; and (4) active ingredient A,alone, followed by active ingredient B, alone, as detailed in Table 8.For treatment regimens (1), (2), and (3), the active ingredients wereapplied to cells for 14 consecutive days. For treatment regimen (4)(sequential regimen), the cells were treated with active ingredient Afor 7 days, followed by treatment with the other active ingredient B for7 days.

TABLE 8 Ex. Active A [A] Active B [B] 14 Niacinamide 0.1% Hexylresorcinol 0.05% 15 TDPA 1% Niacinamide  0.1% 16 TDPA 1%Hexylresorcinol 0.05%

Human 3D MelanoDerm MEL-B skin tissues (available from MatTek, MA) werecultured following the manufacture instructions. Different skin tissuemodels were assigned to one of treatment regimens (1)-(4) as describedabove, with six models allocated to each treatment regimen (i.e., n=6).All active ingredients were prepared as emulsions and applied directlyto the skin models. The specific active ingredients used in each of thefour treatment regimens are provided in Table 8. Following treatment,skin tissue models were collected and the amount of melanin producedfrom the cells was measured using a SOLVABLE melanin assay. Treated skintissues were prepared using a phosphate buffer saline and sodiumbicarbonate. Each skin tissue is added to 500 μl of 0.5 M SOLVABLEsolubilizer (available from Packard BioScience) and incubated at 95°overnight. The absorbance of each skin tissue sample is measured at 490nm and the absorbance is compared to a standard curve to indicate theamount of melanin produced and pigmentation in each skin tissue model.

TABLE 9 A B A + B A/B (% change in (% change in (% change in (% changein Ex. pigmentation) pigmentation) pigmentation) pigmentation) 14 −18.9140.4 95.9 77.8 15 −19.1 −18.9 −24.2 −20.4 16 −19.1 140.4 34.1 39.7

The results for treatments measuring the melanin content produced areshown in Table 9 as a percentage change from control (i.e., untreatedsamples or samples treated with the same emulsion but in absence ofactive ingredients).

Example 17

Hyaluronic Assessment in Human Dermal Fibroblasts in Response to PulsedTreatment Regimens

A series of experiments was conducted to assess the effects of differenttreatment regimens of active ingredients shown in Table 9 on theproduction of hyaluronic acid (HA) in human dermal fibroblast (HDF)cells. Two different treatment regimens were assessed: (1) activeingredient A applied to cells for 12 consecutive days; and (2) activeingredient applied to cells for 2 consecutive days followed byapplication of media not containing active ingredient for twoconsecutive days repeatedly until treatment is applied for 12consecutive days.

Human dermal fibroblast cells were grown in 96-well plates in DMEM media(available from CORNING, N.Y.) supplemented with 10% FBS andL-glutamine. After reaching about 75% confluence, cells were transferredinto DMEM media without FBS, and incubated for 4-6 hours. Differentwells were assigned to one of treatment regimens (1)-(2) as describedabove, with six wells allocated to each treatment regimen. All activeingredients were prepared as emulsions and applied directly to the HDFcells. The specific active ingredients used in each of the two treatmentregimens are provided below in Table 10. Following treatment, cells werecollected and the amount of hyaluronic acid (HA) secreted from the cellswas measured using a commercially available HA assay (available fromCORGENIX Inc., CO).

TABLE 10 % Change in % Change in Active HA over HA over ActiveIngredient Conc. control (daily) control (pulsed) Tiliacora triandra0.05% 184.1 127.7 Niacinamide 0.10% −36.5 1.3 Glycolic Acid 1 mM 9.1 5.1Retinol 1 μM  17.2 32.0 Phytol 0.01% −4.0 25.1

The results are summarized in Table 10 as a percentage change overcontrol (i.e., cells treated with same emulsion but in absence of activeingredients). As shown in Table 10, pulsed treatment of phytol, andretinol resulted in significantly more production of hyaluronic acidthan in daily treatment regimens of actives to HDF cells. Further,pulsed treatment with Tiliacora triandra or glycolic acid was onlyslightly less effective than daily treatment, despite the fact that overthe entire treatment duration, half as much active was used in thepulsed treatment as compared to daily treatment.

As various changes can be made in the above-described subject matterwithout departing from the scope and spirit of the present invention, itis intended that all subject matter contained in the above description,or defined in the appended claims, be interpreted as descriptive andillustrative of the present invention. Many modifications and variationsof the present invention are possible in light of the above teachings.Accordingly, the present description is intended to embrace all suchalternatives, modifications, and variances which fall within the scopeof the appended claims.

The invention claimed is:
 1. A method for diminishing dermatologicalsigns of aging in human skin comprising, in any order, the steps of (1)topically applying to an area of the skin in need thereof, at least oncedaily, a first skin treatment composition comprising, in aphysiologically compatible vehicle, an effective amount of a retinoidfor a first period of time comprising from 6 to 15 days; (2) topicallyapplying to said skin, at least once daily, a second skin treatmentcomposition that is different from said first skin treatment compositionfor a second period of time comprising from 6 to 15 days, said secondskin treatment composition comprising, in a physiologically compatiblevehicle, an effective amount of phytol; and (3) repeating steps (1) and(2) for a number of times sufficient to diminish said dermatologicalsigns of skin aging.
 2. The method according to claim 1, wherein saiddiminishing dermatological signs of aging is selected from the groupconsisting of: (a) treatment, reduction, and/or prevention of fine linesand/or wrinkles; (b) reduction of skin pore size; (c) improvement inskin thickness, plumpness, and/or tautness; (d) improvement in skinsmoothness, suppleness and/or softness; (e) improvement in skin tone,radiance, and/or clarity; (f) improvement in procollagen, and/orcollagen production; (g) improvement in maintenance and remodeling ofelastin; (h) improvement in skin texture and/or promotion ofretexturization; (i) improvement in skin barrier repair and/or function;(j) improvement in appearance of skin contours; (k) restoration of skinluster and/or brightness; (l) replenishment of essential nutrients andor constituents in the skin; (m) improvement of skin appearancedecreased by aging and/or menopause; (n) improvement in skinmoisturization; (o) increase in skin elasticity and/or resiliency; (p)treatment, reduction, and/or prevention of skin sagging; (q) improvementin skin firmness; (r) reduction of pigment spots and/or mottled skin;and (s) improvement of optical properties of skin by light diffractionor reflection.
 3. The method according to claim 1, wherein saiddiminishing dermatological signs of aging comprises a reduction of finelines and/or wrinkles.
 4. The method according to claim 1, wherein saiddiminishing dermatological signs of aging comprises a reduction ofpigment spots and/or mottled skin.
 5. The method according to claim 1,wherein said first period of time is 7 days, and said second period oftime is 7 days.
 6. The method according to claim 1, wherein said firstand second periods of time are consecutive such that one begins on theday following the last day of the other.
 7. The method according toclaim 1, wherein said second skin treatment composition does notcomprise an effective amount of a retinoid.
 8. The method according toclaim 7, wherein said second skin treatment composition comprises one ormore α-hydroxy acids.
 9. The method according to claim 8, wherein saidα-hydroxy acids include one or more of glycolic acid, lactic acid andcitric acid.
 10. The method according to claim 7, wherein said secondskin treatment composition comprises one or more antioxidants.
 11. Themethod according to claim 10, wherein said antioxidants include one ormore of ascorbic acid, beta-carotene, hexylresorcinol, tocopherol andits derivatives, phytanic acid, and thiodipropionic acid and its esters.12. The method according to claim 1, wherein said physiologicallycompatible vehicles are independently in the form of oil-in-wateremulsions, water-in-oil emulsions, aqueous serums, and/or gels.
 13. Themethod according to claim 11, wherein said physiologically compatiblevehicles are each in the form of oil-in-water emulsions comprising from0.01%40% by weight of emulsifier.
 14. The method according to claim 1,wherein said first skin treatment composition comprises from about 0.01%to about 1% by weight retinol, and said second skin treatmentcomposition comprises from about 0.01% to about 10% by weight phytol,from about 0.01% to about 10% by weight glycolic acid, and from about0.01% to about 10% by weight thiodipropionic acid or esters thereof. 15.A method for treating fine lines and/or wrinkles in the skin comprising,in any order, the steps of (1) topically applying to an area of the skinin need thereof at least once daily a first topical compositioncomprising, in a physiologically compatible vehicle, an effective amountof a retinoid for a first period of time comprising from 6 to 15 days;(2) topically applying to the same area of skin at least once daily asecond topical composition that is different than said first topicalcomposition for a second period of time comprising from 6 to 15 days,said second skin treatment composition comprising, in a physiologicallycompatible vehicle, an effective amount of phytol; and (3) repeatingsteps (1) and (2) for a number of times sufficient to reduce theseverity or number of fine lines and/or wrinkles.
 16. The methodaccording to claim 15, wherein steps (1) and (2) are repeated at leastfour times.